Medical Scholars Program

Research Synopsis

Akhtar, Aadeel

State-of-the-art upper limb prostheses are severely limited in their ability to provide sensory feedback to a user. The lack of sensory feedback forces prosthesis users to rely on visual feedback alone in manipulating objects, and often leads to abandonment of the prosthesis in favor of the user’s unimpaired arm. Consequently, there is a critical need to develop mechanisms that enable people with upper limb amputations to be able to receive sensory feedback from the environment. Through the use of techniques like targeted reinnervation, there has been significant progress in providing patients with intuitive neural control of their prostheses as well as sensory feedback. Studies have shown that patients receiving sensory stimulation over reinnervated sites while operating a prosthesis more strongly incorporate the artificial limb into their body schema. However, there is limited cutaneous space available over the reinnervated sites for both EMG sensors and stimulators to be placed. As a result, the overall objective of the proposed research is to clinically evaluate a flexible, stretchable epidermal electronic device that conforms to the skin and can simultaneously record EMG and provide electrotactile sensory stimulation at high density over reinnervated sites. We hypothesize that long-term, closed-loop sensorimotor control in prostheses enabled by epidermal electronics will improve fine motor control and promote incorporation of the prosthesis into the body schema, ultimately reducing prosthesis abandonment. We will address this hypothesis through the following Specific Aims, in which we will 1) optimize and validate a single flexible epidermal device that can both acquire EMG and provide electrical stimulation simultaneously at high density, 2) develop methods for automatic calibration and modulation of electrotactile sensation intensity to enable long-term wear, and 3) improve fine force control, object recognition, and embodiment through the use of sensory feedback. In turn, we expect that daily usage of prosthetic devices will increase due to the incorporation of high resolution sensory feedback.

Arif, Waqar

Non-alcoholic steatohepatitis (NASH) is emerging as one of the most common liver disease in the American population. It is a metabolic disorder in which fat accumulation within the liver (steatosis) is associated with inflammation, hepatic injury and cirrhosis without significant consumption of alcohol. Recent studies estimate this disease affects roughly 6 – 17% of the general population with increased prevalence in individuals affected with obesity and type II diabetes. Of the individuals affected with NASH, about 20 – 25% develop advanced stages of fibrosis eventually leading to liver failure and death. Current knowledge of this disease is limited because early stages (simple steatosis) of NASH are asymptomatic and difficult to detect. Hence, a robust model system is necessary for rapid progress in understanding NASH etiology, progression and potential therapeutic targets.
Surprisingly, preliminary phenotypic characterization of hepatocyte-specific SRSF1 knockout (SRSF1 HKO) mice show all the hallmarks of NASH; steatosis, inflammation and fibrosis. SRSF1 belongs to a highly conserved SR family of pre-mRNA splicing factors that share two modular protein domains; the RNA recognition motif (RRM) and the serine/arginine dipeptide repeat (RS) domain. Initial in-vitro studies of this splicing factor revealed it was essential for correct 5' splice site selection and cleavage. Further studies of this protein revealed it could modulate splicing in a concentration-dependent manner thus making it an alternative splicing factor. Furthermore, SRSF1 is one of the few members in the SR family of proteins, which also has nucleocytoplasmic shuttling activity. Within the cytoplasm, SRSF1 has been shown to regulate both translation and non-sense mediated decay (NMD) of target mRNAs.
Focus of my research is to 1) identify the gene network regulated by SRSF1 and 2) determine how misregulation of this network results in NASH. To gain insight into these question I use a combination of next-generation sequencing techniques (RNA-Seq and iCLIP-Seq), bioinformatics anaylsis, histology, cell culturing, and various molecular biology techniques.

Baldwin, Jennifer L.

Driven by the timeline of the recent US conflicts in Iraq and Afghanistan, the current moment in clinical medicine at Veterans Affairs (VA) hospitals offers an important, circumscribed setting for evaluating both the effects of contemporary US warfare on soldiers and society, as well as personal, biomedical, and bureaucratic efforts to understand and manage these effects within veterans’ lives and on broader social publics. This qualitative study thus evaluates how veterans and VA clinicians at a Midwestern VA Health Care System understand the experiences of mild traumatic brain injuries and post-traumatic stress disorder --the two signature injuries of recent US conflicts -- in relation to an intensification of clinical and scientific surveillance of veterans and these traumatic conditions. This project utilizes ethnographic methodologies to triangulate analyses of a) participant-observation in VA clinical spaces where veterans receive physical and mental health care; b) analysis of the professional micro-practices, clinical sensibilities, and bureaucratic processes revealed in veteran medical records; c) in-depth interviews with veterans and VA clinicians regarding each’s understanding of PTSD and mTBI, and their efforts to manage each; as well as d) emergent biomedical and neuroscientific knowledge and discourses about both diagnoses during these wars.

In ethnographically characterizing the meanings and subjectivities that veterans and clinicians assign each diagnosis, this project provides insight into the forms of subjectivities and citizenships that clinical practices and biomedical knowledges facilitate and impede in veterans’ interactions with the state and negotiation of their traumatic injuries. As such, it tests the degree to which emergent VA biomedical knowledges and practices contribute to novel modes of citizenship as predicted by Foucauldian theories of biopower. This qualitative analysis also permits investigation of other forms of citizenship that disabled veterans enact vis-a-vis the state, and the alternative knowledges, experiences, and social forces that might contribute to them. Thus, this study contributes broader understandings of the subjectivities that are both present and possible for a population that has long been the subject of intense state and medical scrutiny.

By documenting the VA’s bureaucratic model of care and everyday practices that include medical evaluations, diagnosis, and clinical communications, I also characterize the US government’s response to the signature injuries of its recent wars, while simultaneously analyzing the cultural work enacted by the VA. This project suggests that a core function of the VA is to demonstrate a moral performance of care, and that central goals of this performance aim to shape the meaning of war-acquired mTBIs for both the veteran and broader public. Far from the abdication or failure to provide care depicted in popular media and cultural forms, this project reveals the extent to which the VA’s management of war-acquired injuries functions as an intensive, highly orchestrated performance and means of domesticating and mitigating the effects of war when they are brought home. In this way, the medical management of these wars’ signature injuries reflects a politics of care that promotes particular logics of state governance, citizenship, and state responsibility in the management of injured veterans and broader consequences of war. When combined with analysis of biopower’s theoretical relevance to understanding veterans’ on-the-ground experiences with these traumatic injuries, this descriptive analysis of how the state operates through the VA to manage the effects of contemporary warfare advances social scientific understandings of the nature of biopower itself, and its ability to be simultaneously productive and destructive, adaptive and fragile.

Camacho, Mariam

The current most frequently prescribed antidepressants, selective serotonin reuptake inhibitors (SSRIs), work 20-50% of the time, at best. Research in the depression field predominantly focuses on inhibition of feedback regulation of the serotonin system. My project, however, utilizes a unique approach by employing the capabilities of two powerful computational tools in order to understand how SSRIs work and how they can be improved by modeling drug-induced adaptations in the brain across a network of nine different brain regions. This modeling approach ties together a tremendous volume of data from the literature that could not otherwise be analyzed without computational tools due to the sheer magnitude and complexity of the information. Specifically, the programming languages I use are MATLAB and Maude, due to their unique capabilities. MATLAB interprets statements as commands and executes statements in the order that they are given, but Maude has the capability of interpreting statements as facts, and can execute statements in all possible orders generating a searchable state space. My preliminary model generated a testable hypothesis involving a combination of an SSRI and a corticotropin releasing factor receptor 1 (CRF1R) antagonist in order to improve antidepressant efficacy under the assumption of the serotonin hypothesis. More recently, I have increased the number of interactions in the preliminary model by increasing the number of connections between the neurons, and have expanded the model to include more data to justify initial receptor levels. My goal now is to update both the MATLAB and Maude versions of the model and get them to agree (as a crosscheck), then run state-space searches with Maude. The current most frequently prescribed antidepressants, selective serotonin reuptake inhibitors (SSRIs), work 20-50% of the time, at best. Research in the depression field predominantly focuses on inhibition of feedback regulation of the serotonin system. My project, however, utilizes a unique approach by employing the capabilities of two powerful computational tools in order to understand how SSRIs work and how they can be improved by modeling drug-induced adaptations in the brain across a network of nine different brain regions. This modeling approach ties together a tremendous volume of data from the literature that could not otherwise be analyzed without computational tools due to the sheer magnitude and complexity of the information. Specifically, the programming languages I use are MATLAB and Maude, due to their unique capabilities. MATLAB interprets statements as commands and executes statements in the order that they are given, but Maude has the capability of interpreting statements as facts, and can execute statements in all possible orders generating a searchable state space. My preliminary model generated a testable hypothesis involving a combination of an SSRI and a corticotropin releasing factor receptor 1 (CRF1R) antagonist in order to improve antidepressant efficacy under the assumption of the serotonin hypothesis. More recently, I have increased the number of interactions in the preliminary model by increasing the number of connections between the neurons, and have expanded the model to include more data to justify initial receptor levels. My goal now is to update both the MATLAB and Maude versions of the model and get them to agree (as a crosscheck), then run state-space searches with Maude.

Cangellaris, Olivia V.

I utilize a semi-conductor based technology to culture rat hippocampal neurons for enhanced control over neural circuit development. The substrate contains an array of flexible, biocompatible microtubes. These microtubes are composed of an ultra-thin nanomembrane of oppositely strained layers that self-roll (self-rolled-up membranes, S-RuMs). The microtubes can be fabricated with metal in the inner diameter that acts as an electrode to support electrical stimulation. By culturing the neurons on this substrate, I am able to characterize how the microtubes impact neuronal alignment, and through application of electric stimulation, further explore how this substrate can be used to drive neuronal growth and behavior. Future applications of this technology can facilitate neuroregenerative solutions, particularly in the peripheral nervous system by enabling neural repair as a supportive scaffold functionalized with positive chemical cues, electrical stimulation to drive outgrowth of neurites, and recording capabilities to assess functionality.

Derk, Gwendolyn R.

In brief, the kidneys are responsible for blood purification and fluid excretion. When the kidneys begin to fail, fluid builds up in the cardiovascular system, a closed loop system. This results in higher blood pressure. Most patients who begin hemodialysis are on 4+ anti-hypertensive medications. These medications keep the blood vessels dilated and prevent the body's normal response to fluid loss. During dialysis treatment, LITERS of fluid are removed from a patient's circulation system over 3-4 hours. Patients on multiple anti-hypertensive medications less able to tolerate this fluid removal and therefore have more volume overload, higher mortality, and worse outcomes. Thus, I have developed a protocol to deprescribe these medications gradually and in a systematic order. We are currently testing this protocol and believe that is will not only help guide physicians to find the best individual fit for their patients but also improve their patients' quality of life and outcomes.

Dostal, Carlos R.

Stress and inflammation are intimately related adaptive responses to pathogens or other stressors which upset our body's homeostasis. However, when illnesses, infections or stressors persist--or are sufficiently traumatic--our normally adaptive responses can become maladaptive compromising both our immune system and mental wellbeing. Depression accounts for roughly 33% of mental illnesses which are the leading cause of disability worldwide. Recent studies have outlined biological mechanisms by which stressors--inducing either proinflammatory cytokines or glucocorticoids--illicit symptoms of depression. Central to this hypothesis are the glucocorticoid and cytokine inducible enzymes tryptophan and indoleamine 2,3-dioxygenases (DOs: Tdo2, Ido1 and Ido2). The DOs are rate-limiting for tryptophan metabolism down its dominant metabolic pathway, the Kynurenine Pathway. While accumulating evidence supports an interconnection between symptoms of depression and increased Kynurenine Pathway activity, the cellular specificity underpinning DO regulation by stress and inflammation remain poorly defined. Thus, this thesis probes the regulation of DO expression by acute stress, and by interactions of peripheral inflammation and exogenous glucocorticoids within the mouse brain, astrocytes, microglia, and peripheral tissues. We identify a unique role for astrocytes in the DO response to acute stress devoid of DO regulation within microglia, and describe unique regulation patterns for both astrocytes and microglia in the DO response to peripheral inflammation and exogenous glucocorticoid. Importantly, these data determine that glucocorticoids fail to suppress inflammation-induced DOs with the brain. Finally, the cell-specific contributions of myeloid- and neuron-derived Ido1 to inflammation-induced anhedonia-like behavior are investigated using Cre-lox mediated cell-specific knockdown of Ido1 in mice. Our results strongly suggest myeloid derived cells contribute to inflammation-induced anhedonia. Together, the data highlight glia and tissue-specific DO regulation by stress and inflammation, and cell-specific contributions of Ido1 to inflammation-induced anhedonia-like behaviors of mice.

Erickson, Hanna L.

Scaffold proteins provide efficiency and specificity to an otherwise well-mixed cell. These are generally large protein molecules with multiple binding domains that interact with signaling and structural proteins and organize them within space and time. IQGAP1 is a particularly large and remarkably complex scaffold protein that is evolutionarily conserved and ubiquitously expressed. Its five binding domains interact with over 140 proteins, and it is involved in processes including proliferation, cytoskeletal regulation, migration, cell adhesion, and extracellular signaling. A large body of evidence supports IQGAP1 as a tumor promoter, though there is some data to suggest that in certain circumstances IQGAP1 can function to suppress tumor development. This contradictory evidence highlights the need to understand how physiological context can affect scaffold protein function.

My PhD research aims to identify the role of IQGAP1 in regulating liver physiology. Our lab previously found that hepatic IQGAP1 expression is induced by bile acids, which precedes formation of aggressive liver tumors. As bile acids are physiological signaling molecules that can reach pathological levels in liver disease, I am assessing IQGAP1 function in the liver along a spectrum of health and disease, from regulating the response to changes in nutrition status to mediating the response to liver injury and promoting tumor development. My research has shown that IQGAP1 is required for proper responses to nutritional stresses such as fasting and ketogenic diet, which is in part due to its regulation of the major nutrient sensor mechanistic target of rapamycin (mTOR). Additionally, I have shown that re-expressing IQGAP1 in IQGAP1-null livers can restore bile acid-induced liver proliferation and loss of IQGAP1 results in more severe liver damage when mice are treated with a liver toxin. I am also performing tumor studies to identify whether loss of IQGAP1 can reduce tumor growth in a chemically-induced model of liver cancer. Together, my research has shown that, despite having low baseline expression in the liver, IQGAP1 not only does impact liver biology, it may have both beneficial and detrimental effects.

Gates-Tanzer, Lauren T.

Cellular FLICE inhibitory protein (cFLIP) is a FLIP protein originally characterized for its extrinsic anti-apoptotic function. We recently showed that cFLIPL has a second function; it inhibits IRF3 activation. IRF3 is a transcription factor that controls the expression of IFNβ and other anti-viral proteins. It is unknown how cFLIPL inhibits IRF3 activation. The goal of this project is to characterize the mechanism of inhibition of IRF3 by cFLIPL. Our initial approach used over-expression of MAVS, TBK1, or a constitutively active IRF3 mutant, IRF3CA, to trigger IRF3 activation in cells over- expressing wild-type or mutant cFLIPL proteins. IRF3 activation was evaluated by using a luciferase reporter assay. These data suggested that cFLIPL functioned at a step after IRF3 dimerization in the IRF3 activation pathway. Our data showed that the caspase-like domain, but not the DEDs of cFLIPL were sufficient for IRF3 inhibitory function. Further, preliminary data suggest that cFLIPL and the CLD mutant inhibit IRF3/CBP interaction upon stimulation, but cFLIPS lacking the CLD does not. Our current hypothesis is that IRF3/FLIP interactions disrupt IRF3/CBP interactions and as a result the transcription factor cannot bind its promoter target. Further experiments are being conducted to evaluate this hypothesis.

Kaylan, Kerim B.

Engineered systems provide a means of deconstructing the microenvironmental cues which guide cell fate and function. These cues can include biochemical elements, as in ligand-receptor binding for cell-cell or cell-extracellular matrix (ECM) interactions, or responses to biophysical parameters, as in cell sensing of substrate material properties. One category of engineered system, high-throughput cell microarrays, are useful not only for the efficient identification of roles for new cues in specific biological processes but also for mapping combinatorial interactions between known cues. In this dissertation, I describe a cell microarray platform with several additional capabilities: the integration of multiple readout modalities, including direct readout of mRNA expression using in situ hybridization and, crucially, cell-generated forces using traction force microscopy (TFM); and the deconvolution of signaling via cell-cell (ligand-receptor) interactions by combining cell-extrinsic ligand presentation with cell-intrinsic ligand knockdown. I delineate the use of this platform towards investigations of microenvironmental regulation in the context of liver progenitor differentiation and lung tumor cell drug responses. Liver progenitor differentiation was found to be combinatorially regulated by Notch, TGFβ signaling as well as interactions with ECM proteins. The Notch ligands Jag1 and Dll1 were further found to found play distinct cell-intrinsic and cell-extrinsic roles in differentiation towards a biliary epithelial cell fate. Parallel TFM measurements in arrayed microenvironments indicated that progenitor cell differentiation towards biliary fates is a coordinated function of ECM composition, substrate stiffness, and cell contractility. Additional analysis of spatially-localized differentiation within array patterns showed that cooperative interactions between Notch and cell mechanotransduction signaling pathways are necessary for biliary differentiation. Similarly, the responses of tumor cells to drug treatment is known to depend on interactions with their matrix microenvironment. Lung tumor cell drug responses were mapped using a combinatorial ECM array design and shown to be a function not only of matrix composition but also genotype, specifically the presence or absence of the lineage oncogene ASCL1. Thus, this dissertation presents an advanced array platform which not only improves our understanding of biochemical and biophysical regulation of liver progenitor fate specification and lung tumor cell drug responses but also enables similar studies of other tissue contexts and organ systems.

Kim, Grace S.

Post-traumatic stress disorder (PTSD) is a common and debilitating mental disorder precipitated by trauma exposure. While most individuals are exposed to a potentially traumatic event at some point in their lives, only a small subset develop PTSD This suggests that trauma exposure is necessary, but not sufficient, for the pathogenesis of PTSD, and that many other pre-existing factors, including genetic background, play an influential role in determining individual response to trauma. In my research, I focus on examining transcriptomic profiles that reflect the pathophysiology of PTSD. Since this biological correlate culminates the effects of functional genetic variants and regulatory epigenetic marks, I explore the genomic and epigenomic players underlying leukocyte transcriptomic profiles in PTSD to gain a systems-level understanding of the mechanisms involved in this disorder. Additionally, I consider fundamental population contexts and sources of heterogeneity that have not been adequately addressed in the existing PTSD literature – sex, ancestry, and cell composition.

Konopka, Christian J.

In this project we are developing a means of detecting, monitoring and treating prostate cancer. Our lab has previously assisted in developing a strategy for therapy, based on silencing the expression of the Receptor for Advanced Glycation End Products (RAGE). This therapy resulted in a RAGE-dependent inhibitory effect on the proliferation of both androgen-dependent and androgen-independent prostate cancer cells, cell death, and diminished tumor size in vivo. Due to the significant heterogeneity of prostate cancer, molecular imaging is expected to play an important role in the evaluation of this disease and predicting the efficacy of therapeutic interventions.
Therefore, this project’s overarching goal is to design a non-invasive RAGE-targeted multimodal imaging agent that will be used in PET/CT and optical imaging to improve the diagnosis of prostate cancer, provide sensitive and selective predictions of the success of anti-RAGE therapies, and enable monitoring of the outcomes of these therapies. We also will use this imaging agent to enhance current surgical processes, by developing an image guided system where a surgeon can visualize and manipulate a tumor with 3-D PET/CT images to optimize his surgical route and efficiency and also optically image the tumor in vivo during the surgical process. We hypothesize that non-invasive hybrid PET-CT imaging with RAGE-targeted probes, in combination with both postmortem histochemical analysis of the RAGE, and the development of our novel image-guided surgery strategy will contribute significantly to every clinical phase of prostate cancer evaluation, the assessment of targeted anti-RAGE treatment, and the efficacy of surgical intervention. Moreover, we postulate that RAGE-targeted imaging strategy could provide selective prediction of the success of novel anti-RAGE therapies and enable early determination of responders and non-responders to anti-RAGE interventions.

Kwon, Lydia E.

I am currently developing a microfluidic device to detect serum biomarkers indicative of human papillomavirus (HPV)-related oropharyngeal cancer (OPC). The device incorporates a photonic crystal platform whose special structure and composition enhance the fluorescence from the detection molecules, resulting in a stronger signal than that from traditional platforms. Unlike current detection methods which require a biopsy and/or RNA sequencing, this method would be relatively short (<5 hours) and minimally invasive, as it requires only a couple drops of blood. The photonic crystal enhanced fluorescence (PCEF) also lends to a high detection sensitivity, meaning very low concentrations of biomarkers can be detected. The hope is to use this device to detect cancer biomarkers from serum at earlier stages, when treatments have higher efficacy but the biomarker concentration is lower and more difficult to detect using traditional methods.

Liu, Siyuan C.

I an building a robot out of cells, otherwise known as a biobot. We have taken rat spinal cords and combined them with strips of muscle grown in lab. They are placed on an engineered platform and allowed to grow and move.

The science underlying this new technology is understanding how neurons and glia interact to process information from the outside world and tell muscles what to do. We look at how neurons respond to signals around them and how glia regulate and control neuronal growth. This can help us to create a better biobot for future use in labs as a diagnostic and testing platform for new drugs, to introduce into the environment to clean up biological waste, and to understand how our brains and nervous systems developed into complex life.

Livnat, Itamar

Nervous system cells use a large variety of chemicals in order to communicate and coordinate for complex processes. One class of chemicals, known as neuropeptides, are composed of a chain of smaller units called amino acids. These amino acids have an interesting characteristic known as chirality, a concept where each of these amino acids have a mirror image that is in every other way identical to them, not unlike left and right hands. The left-handed versions are known as L-amino acids, while the right-handed versions are known as D-amino acids. L-amino acids are chosen by biology to form these neuropeptides during their initial production, a process called translation. While translation uses only L-amino acids, further modifications can be made after this process, including conversion of one these amino acids into a D-amino acids. For example, a peptide of four amino acids (LLLL) can be converted into a peptide containing one D-amino acid (LDLL for example). This has a functional consequence, such that in many cases, the neuropeptide with the D-amino acid is biologically active with the neuropeptide with only L-amino acids is not. Because these amino acids identical in every way except that they are mirror images, this modification can be very difficult to detect; the consequence of this is that it is not yet recognized as a widespread phenomenon. Thus, when pharmaceutical companies spend time and resources developing drugs to target the biological activities of neuropeptides, they synthetically prepare the peptide using only L-amino acids. If D-amino acids do exist in neuropeptides, there is a chance that some studies are wasted efforts and missing out on potential therapeutics for nervous system diseases.
To address the difficulty in detecting D-amino acids in neuropeptides, I have been working on a method that we call a D-amino acid-containing neuropeptide discovery funnel. This funnel can work in a complex peptide mixture; the technology and method are being developed using the nervous system of a mollusk, Aplysia californica. This is a good model for studying these peptides because its peptides are rather well-characterized and two D-amino acid-containing neuropeptides have already been identified in this organism. There are three steps in the discovery funnel. The first step screens for peptides potentially containing D-amino acids by their ability to resist degradation by specific enzymes (D-amino acid-containing neuropeptides are difficult to degrade). In the second step, the chirality of each amino acid is investigated using a specific chemical tag than can help differentiate the two, after breaking the neuropeptide down into its component amino acids. Finally, these peptides are synthetically prepared with the D-amino acid at the suspected position and tested to see if this is the bioactive form. The hope is to investigate other model nervous systems, like rodent nervous systems, to establish that this is a more widespread phenomenon than currently believed. This can help shape future pharmaceutical studies in nervous system disorders.

Long, Kenneth

As part of the Nano Sensors Group, I work on two projects using optical techniques to measure biologically relevant samples. I currently use a Photonic Crystal Enhanced Microscope to study non-invasively the cell-substrate interactions of adherent cell lines to investigate important processes such as stem cell migration and cancer cell metastasis. Additionally, i work to use a smartphone based biosensor developed as a mobile spectrometer to perform traditional laboratory assays in non-laboratory settings.

Magerko, Katherine A.

Broadly speaking, my research focuses on risk and resilience factors related to health of families and children/young adults in varying contexts. We are working on several projects toward this end. As a part of the UP AMIGOS project, we are looking at the metabolic consequences of stressors and depression in young adults in Mexico with a particular interest in insulin sensitivity related outcomes. Under the umbrella of the STRONG KIDS project, we are looking at how pediatricians may impact early childhood physical activity through what they say to parents about physical activity at well-child visits. Additionally, we are working with the Division of Specialized Care for Children in Chicago to analyze their data from the state of Illinois on families with children that have special health care needs. I am also helping with an initiative on campus to bring together resources to help researches with projects related to immigrant health and am working on bringing together census data for a policy report to help when sampling for such studies.

Finally, my dissertation work is on health in the family child care context. Family child care, care that takes place in a child care provider's own home, is an understudied area in the literature. What little literature does exist suggests that child care providers may have worse health outcomes even than sociodemographically matched samples. We hope to add to the literature by doing the first in-depth study on family child care provider health with the broader goal being to inform the creation of an intervention that can be used by child care resource and referral offices across the state.

Mailing, Lucy J.

The goal of my project is to determine how diet and exercise can be used to modulate the gut and skin microbiome and to better understand how these microbial communities interface with the immune system and one another. Ultimately, I hope to provide evidence for the existence of a gut-skin axis and identify lifestyle interventions that can improve gut and skin barrier function and clinical symptoms in conditions like inflammatory bowel disease and atopic dermatitis.

Majdak, Petra

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder which manifests as deficits in impulse control, excessive activity in home or school settings, and an inability to focus attention on relevant stimuli. While millions of individuals with ADHD lack this ability to effectively modulate behaviors and optimize societal, academic, or occupational performance, surprisingly little is known regarding its genetic etiology and few improvements in therapeutics have been accomplished over the past decades. This lack of progress is partly attributable to the dearth of genetic models of ADHD enabling unbiased exploration of the genetic architecture of hyperactive-impulsive behavior. The goal of my dissertation is to fill this critical need for a genetic model which may be used to meaningfully advance the field of ADHD research. Toward that end, I systemically evaluated the face, construct, and predictive validity of a genetically variable line mice selectively bred for increased home cage activity in order to determine whether it may faithfully recapitulate facets of ADHD symptomatology.

We obtained promising results from our initial foray into assessing the predictive validity of the line; High-Active mice demonstrate home cage hyperactivity which is paradoxically ameliorated by chronic low-dose amphetamine. Furthermore I establish a statistical procedure for estimating whether line differences are due to selection for hyperactivity versus genetic drift; results suggest the genetic underpinnings of home cage hyperactivity are unique and likely differ from those mediating other forms of increased physical activity. I then expound on the face validity of the line by confirming the hyperactivity and motor impulsivity of the High-Active line in two different versions of the operant Go/No-go task and within adolescent males and adult females. Interestingly, the High-Active line shows little evidence of inattention as assessed by spontaneous alternation in the Y-maze, suggesting High-Active validity may be circumscribed to the Hyperactive-Impulsive subtype of ADHD. Furthermore the predictive validity of the line is reaffirmed in this chapter as the same low-dose amphetamine which reduces hyperactivity also paradoxically ameliorates motor impulsivity. Analysis of regional neural activation of High-Active versus Control mice at baseline and in response to low-dose amphetamine indicates dysregulated prefrontal cortex and cerebellum may partly modulate High-Active impulsive behavior. I then address a fundamental question regarding the construct validity of the High-Active line. In this large-scale cross-fostering experiment I demonstrate that the significant deficits in the maternal competence of High-Active dams do not influence the hyperactivity of High-Active offspring; raw genetics mediate this transgenerational phenotype whose expression cannot be influenced even by the most stressful of perinatal environments. I further infer
evidence of extreme dopaminergic dysregulation in the High-Active line, as only a genetic ablation of the dopamine transporter has produced dams which even somewhat approach the severity of High-Active deficits in maternal care. Finally, high-yield uses of this now-validated model of ADHD include strategies for uncovering relevant genetic etiological factors, identifying novel compounds to advance therapeutic approaches, and elucidating endophenotypes which may aid in the diagnosis of ADHD. Ultimately the efforts of this dissertation have culminated in a validated genetic model of Hyperactive-Impulsive ADHD which is poised to serve as a platform for significantly advancing our understanding of this ubiquitous, heritable behavioral disorder.

Palazzolo Ray, Andrea M.

In the case of polypeptides, oligonucleotides, and oligosaccharides the creation of automated synthesis platforms had a transformative impact on understanding and optimizing the function of these macromolecules. In each of these cases the automated synthesis platform was enabled by a general building block-based approach with a defined set of building blocks and a general purification method for all of the corresponding intermediates. In the case of small molecules, no such platform exists. Despite years of progress, the synthesis of small molecules is highly customized and minimally flexible prohibiting the automated synthesis. As a result, small molecule synthesis remains the bottleneck in the discovery and optimization of their functional potential.

Despite this fact, natural products are derived from five major biosynthetic classes each of which utilizes a small number of reactions to assemble a defined set of building blocks. Importantly, even complex Csp3 rich polycyclic natural products are biosynthesized through iterative building block assembly to form a modular linear precursor, which is then cyclized to afford the natural product. We thus hypothesized whether a general and automated building block based approach could be utilized in the synthesis of most natural products.

Using the iterative assembly of MIDA boronate building blocks, we recently showed that many distinct natural products using one automated synthesis platform. I am working to extend this platform through the systematic analysis of terpene-derived natural products to enable their automated assembly.

Sanders, Richard N.

My dissertation approaches holistic medicine as a part-whole problem, arguing that no matter the parts of the interdisciplinary amalgamation of knowledge from which a holistic model of healthcare might be developed, the combination would not constitute an integrated whole. The first part of the dissertation focuses on one reason why: disciplinary fragmentation. Disciplinary fragmentation is modeled by the Biglan schema of disciplinary difference. The Biglan schema appeared in 1973 as a study of subject-matter difference and formalized three pairs of categories that have since functioned as a de facto system of disciplinary classification: applied-pure; hard-soft; life-non-life. By articulating how the institutional practices comprising medical research, patient care and medical education enact these categories, I show how disciplinary fragmentation creates conditions that are not amenable to holistic healthcare. In the effort to create conditions that would be, I look in the dissertation's second part to recast the Biglan categories by further developing the integrative approach advanced by cognitive scientist Douglas Hofstadter's 1979, Pulitzer Prize-winning text Gödel, Escher, Bach (GEB). Wrestling with the perennial question of how animate beings arise from inanimate matter, GEB's proposed answer revolves around two recursive patterns that Hofstadter calls strange loops and tangled hierarchies. These two patterns, along with a third, rhythmic braids, represent the dissertation's reconstitution of the hard-soft, applied-pure and life-non-life categories, respectively. It is through this reconstitution that the rudiments of an integrative method - one that reorganizes without distorting the knowledge produced under past disciplinary rubrics -- might emerge. The dissertation concludes with the proposal that the practice of holistic medicine presupposes a reflective process whereby knowledge traditions are reconciled.

Sawicki, Elizabeth G.

Ischemic stroke is a leading cause of death and adult disability. However, there are few effective treatments currently available and many patients do not reach the hospital in time to receive them. More patient-friendly options to reduce brain damage and improve functional recovery following a stroke are needed. One such solution is to use nanotechnology to deliver a drug intranasally, a method that is simple and convenient for patients. We are interested in studying how nanotechnology can improve a drug's ability to heal the brain following a stroke.

We have previously shown that gelatin nanoparticles can significantly improve the ability of an intranasally administered drug to heal damaged brain tissue following a stroke. However, we do not completely understand which properties of gelatin nanoparticles are most important for improving the healing process. We believe the key factor is the nanoparticle's ability to concentrate a drug in the damaged brain regions. Therefore, we are using mice to study how gelatin nanoparticles travel through the brain and degrade after nasal administration. By better understanding how gelatin nanoparticles behave in normal and damaged brains we hope to be able to further improve the gelatin nanoparticles' ability to heal the brain following a stroke.

Tencati, Michael J.

Yersinia pestis is the causative agent of bubonic, septicemic, and pneumonic plague. This pathogen subverts the immune response of its host by several different mechanisms, however some hosts resist infection, and this resistance has been found to be heritable. Our lab has focused on inbred strains of mice and found several that show resistance in a pgm- plague model. By breeding the resistant mice with mice that are susceptible and then screening the offspring for novel crossovers I create new lines which are then tested for either maintenance or loss of resistance. In this way we have been attempting to determine which genes may play a role in conferring resistance to plague. We have mainly been following two separate loci, one on chromosome 1 of mice of the 129 background, and a second on chromosome 17 in Balb/cJ mice. In order to look at the molecular basis of resistance we have been isolating different cell types and testing the ability of each to either control bacterial growth or kill Y. pestis.

Updyke, Erin A.

My main research interest is the interface between the ecology and epidemiology of vector-borne disease. Specifically, my dissertation focuses on the eco-epidemiology of Chagas disease in Panama. Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is transmitted by several species of blood-feeding insect in the subfamily Triatominae (Hemiptera: Reduviidae). Many of these species are considered sylvatic, meaning they live the majority of their lifecycle outside human contact, and these species are often considered only incidental or spillover vectors of disease. I am interested in better understanding the epidemiological risk factors associated with Chagas disease transmission as well as the potential impact of sylvatic species of triatomine vectors to household transmission across an urban-to-rural human land-use gradient in Panama Province, Panama.

Waldemer-Streyer, Rachel J.

My research focuses on the cell signaling mechanisms that influence skeletal muscle development. Mature skeletal muscle tissue contains a resident population of stem cells that imparts a great capacity for regeneration. Upon injury, these satellite cells are reactivated and begin to proliferate to dramatically increase myoblast numbers. Effective myogenesis depends on the daughter myoblasts successfully differentiating and fusing with each other to regenerate the characteristic multinucleated skeletal myofibers. Dysregulation of these processes can have severe consequences, including disease states like the muscular dystrophies and cachexia. However, despite the great deal of potential clinical gain in understanding myogenesis, the complex mechanisms underlying skeletal muscle dynamics are still poorly understood.

Cell-secreted factors, such as cytokines and chemokines, represent one possible source of myogenic regulation. It is generally accepted that those factors influencing muscle cell regeneration in vivo are largely of immune cell origin. However, various mass spectrometry analyses have shown muscle cells to be prolific secretors of a wide variety of proteins. These observations point toward the intriguing possibility that muscle cells secrete cytokines that influence their own development and regeneration. To investigate this idea, we conducted an shRNA screen of myocyte-secreted factors that play a role in muscle differentiation. We found 30 cytokines and chemokines that positively or negatively regulate myogenesis, several of which are currently under investigation for their role in skeletal muscle regeneration in vivo.

Wang, Anthony A.

Childhood obesity is a nutrition-related disease with multiple underlying etiologies. The gut microbiota is thought to be a contributor in the development of obesity by fermentation of non-digestible polysaccharides to short chain fatty acids (SCFA), which increases host capacity for energy harvest and storage. Several genes encoding SCFA receptors and transporters, as well as other host responders to gut microbiota have been described. However, the collective impact of common genetic variations (single nucleotide polymorphisms [SNP]) in these genes on obesity phenotypes has yet to be examined in humans. Our hypothesis is that genetic variation in SCFA recognition pathways are related to excess weight gain and microbial distinct profiles are associated with overweight and obesity in children. This proposal will also use a unique approach in studying the relationship between gut microbiota and obesity by evaluating both traditional anthropometric measurements and percent body fat measured by dual energy x-ray absorptiometry (DXA).

This approach here may reveal novel biomarkers for obesity susceptibility at an early age. Analysis of genetic factors will provide needed information for the development of early detection methods including genetic screening for obesity risk. Additionally, an understanding of key microbial players and the metabolites they produce in the gut of children with normal or high BMI and percent body fat will pave the way for therapeutics designed to achieve and maintain optimal gut health.

Zamroziewicz, Marta K.

My research interests lie at the intersection of nutrition and cognitive neuroscience, and focus on the neural and neuropsychological effects of nutrition. My work is motivated by the question of how dietary nutrient intake may impact cognitive processes and the underlying neural structures in humans. Ultimately, I’d like to understand how we could best utilize diet to both prevent deterioration of cognitive function associated with brain aging or dysfunction as well as enhance cognitive function in healthy individuals.