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Biological and Health Sciences

Pre-doctoral fellows have been nominated by their programs and are selected through a competitive review process based on the creativity and impact of the research they are pursuing. The abstracts for recipients in the biological and health sciences describe the framework, aims, and significance of each fellow’s dissertation and demonstrate the breadth of Rackham doctoral programs.

Generation of Sparse, Combinatorial Wiring in Sensory Coding
Maria Ahmed, Molecular, Cellular and Developmental Biology

We experience countless sensory cues on a day-to-day basis. How does the brain cope with this diversity with a limited set of neurons? To do this, neurons in sensory perception and learning regions receive information about cues in combinations. However, the role for sparse, combinatorial connectivity patterns in sensory coding has not been tested experimentally. Using the numerically simpler perceptual and learning center in the fruit fly brain called the mushroom body (MB), my project aims to test this relationship between circuit architecture and function. Within the MB, Kenyon cells (KCs) receive divergent inputs from projection neurons (PNs) that bring in odor information. Using molecular and chemical methods, I aim to change the connectivity density between PNs and KCs. Subsequently, by observing KC odor responses and learning behavior in these flies, I will be able to functionally test the significance of sparse wiring in sensory coding.

Synthesis of Cardiotonic Steroids Oleandrin and Beaumontoside
Nolan Carney, Chemical Biology

Cardiotonic steroids are a broad group of natural products that vary in chemical functionality and biological activity. Two steroids of interest are oleandrin and beaumontoside. Oleandrin is currently obtained through extraction from Nerium oleander and beaumontoside is not commercially available. Oleandrin is of interest for its anti-viral properties including treating flu like symptoms, reducing SARS-CoV-2 levels by 3000-fold in golden hamsters. Our group is interested in oleandrin’s use in treating Alzheimer’s disease using its ability to cross the blood brain barrier and reducing cellular prion protein levels. We developed the first synthesis of oleandrin and beaumontoside for them to be investigated as therapeutics and accessible for synthetic production. Future studies will allow for derivatives to be synthesized in hopes of a suitable treatment for Alzheimer’s disease.

Two Biostatistical Problems
Elizabeth Chase, Biostatistics

Biomedical data often exhibit jumps, which are challenging to model. In the first project, we introduce horseshoe process regression (HPR) to model data with jumps. We use the horseshoe process as a Bayesian prior for a nonlinear association. We find that HPR fits jumpy functions well. In the second project, we extend HPR for repeated measurements. We leverage a Bayesian imputation approach to share information across patients. We use the extension of HPR to model the PSA trajectory over time of prostate cancer patients treated with prostatectomy and salvage radiotherapy. In the third project, we extend an imputation approach for survival data to incorporate propensity weights. We explore best practices for incorporating propensity weights in the imputation procedure, both unclustered and in the presence of clustering. We use the method to estimate the cumulative incidence and key predictors of equipment failure among patients receiving extracorporeal membranous oxygenation.

Genetic Coordination of Subplate-Dependent Neural Circuit Development
Daniel Doyle, Neuroscience

The remarkable cognitive, perceptive, and motor capabilities of the mammalian cerebral cortex depend on correct assembly of neural circuits during development. The wiring of cortical circuits is orchestrated by subplate neurons, which direct axon guidance at the interface of cortical grey and white matter. The genes underpinning the indispensable circuit assembly functions of subplate neurons have remained elusive, due to a lack of precise genetic access to subplate neurons during fetal development. Having pioneered a genetic approach to access subplate neurons at early fetal ages, I identified the first genetic regulator of subplate neuron-dependent circuit wiring. I further discovered essential roles for subplate neurons in the formation of the corpus callosum and corticospinal tract. My work elucidates the genetic mechanisms of neural circuit development, provides a technical framework for future genetic studies of subplate-dependent circuit wiring, and implicates subplate dysfunction as a potential contributor to circuit defects in neurodevelopmental disorders.

The Role of Type I Interferons in Ultraviolet B Light-Induced Keratinocyte Death
Shannon Estadt, Immunology

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect any organ, including the skin. A characteristic feature of SLE is photosensitivity, where exposure to minimal amounts of sunlight or ultraviolet radiation (UVR) triggers cutaneous and systemic disease flares. Despite the importance of photosensitivity in SLE, the responsible mechanisms are not characterized. Type I interferons (IFNs) are overexpressed in non-lesional SLE skin and promote death of SLE keratinocytes after UVR, but the way they do so is unknown. This study explores activation and regulation of cell death pathways in keratinocytes exposed to type I IFNs and UVR. Our data suggests that photosensitive responses exhibited by SLE patients result from type I IFN priming of keratinocytes that sensitizes cells to undergo increased caspase 8-dependent extrinsic apoptosis independent of known death ligands. Continued investigation into mechanisms by which this occurs will provide important prophylactic options to prevent SLE flares and damage.

Revealing Structural Insights into the Regulation of Myosin V Motor-Cargo Complex Assembly
Hye Jee (Lily) Hahn, Cell and Developmental Biology

Cells have distinct architecture, which underlie specialized functions. To establish this organization, Myosin‐V motor proteins actively transport cargoes via the attachment of adaptor proteins. Intracellular transport is fundamental to neurological development and cancer metabolism. Here, I identified specific amino acids within the vacuole specific adaptor Vac17 that bind directly to Myosin‐V. In addition, I identified two new domains on Vac17 of previously unknown function. One domain, coiled‐coil 1, is required for the association of Myosin‐V to the vacuole. The function of coiled‐coil 1 was verified in vivo analysis visualizing vacuole movement, with in vitro assays showing that the presence of coiled‐coil 1 stabilized the recombinant Myo2‐Vac17 subcomplex. In vivo studies were used to demonstrate that the second domain, coiled‐coil 2, is required for Vac17 localization to the vacuole. Identification of new contact sites and domains on the adaptor protein provides insights into how molecular motors interact with cargoes.

Neutrophil Migration and Recruitment Toward Breast Cancer Tumors
Lauren Hein, Cancer Biology

During tumor development, neutrophils and other immune cells infiltrate the tumor niche. Neutrophils have been shown to have primarily pro-tumorigenic effects—a phenotype that can be skewed by transforming growth factor-β (TGF-β), which is present in the tumor microenvironment (TME). Neutrophils migrate to tumors by sensing chemical gradients produced by tumor cells. Our group has shown that highly invasive breast cancer cells secrete factors, including high levels of TGF-β and chemokines, that work cooperatively to activate migration in neutrophils. Although chemokines are known for causing neutrophil migration, the mechanism by which TGF-β mediates neutrophil migration is unknown. Ongoing work is aimed at elucidating how TGF-β works with chemokines to affect neutrophil function. We envision that understanding TGF-β signaling in neutrophils, particularly in the context of cancer, will allow for the development of therapies aimed at inhibiting neutrophil trafficking to tumors.

Sodium Channel SCN8A as a Target for Antiepileptic Therapy
Sophie Hill, Neuroscience

My dissertation will assess the neuronal voltage-gated sodium channel gene SCN8A as a target for treatment of genetic epilepsy. Nav1.6, the protein product of SCN8A, is a key regulator of neuronal excitability. We have demonstrated that reduction of Scn8a expression by administration of an antisense oligonucleotide (ASO) is protective against seizures and death in mouse models of SCN8A gain-of-function and SCN1A loss-of-function. My dissertation will build upon these findings to assess the viability of antiepileptic therapies targeting SCN8A. In Aim 1, I will assess the efficacy of ASO-mediated Scn8a knockdown in four mouse models of epilepsy with different genetic etiologies. In Aim 2, I will administer the Scn8a ASO after seizure onset to mimic the clinical situation. In Aim 3, I will identify transcriptional changes caused by expression of an epilepsy-causing Scn8a mutation. My dissertation will explore new targets and treatments for a common and severe medical problem.

Data Integration for Survival Analysis
Fatema Shafie Khorassani, Biostatistics

Despite significant reductions in cancer mortality over the past three decades, racial disparities in cancer-specific mortality persist. Many factors may confound the association between race and cancer-specific mortality, including demographics, healthcare access, socioeconomic status, and comorbidities. Existing national cancer surveillance databases each collect only parts of this information. When estimating disparities in cancer mortality, using the National Cancer Institute’s Surveillance, Epidemiology, and End Results registry means excluding information on important potential confounders like hospital type, insurance status, and comorbidities. On the other hand, the National Cancer Database, which does provide those variables, excludes cause-of-death information, making it impossible to study cancer-specific mortality. Integrating data from multiple sources allows us to study associations between race and cancer-specific mortality over time adjusted for important confounders. In this dissertation, I propose novel statistical methods for integrating datasets for survival analysis, motivated by studying racial disparities in cancer-specific mortality.

Improved Pain Therapies Using Allosteric Modulation
Kelsey Kochan, Pharmacology

Opioid therapeutics, such as morphine, that act at the mu-opioid receptor (MOR) are the clinical standard for patients struggling to manage symptoms associated with pain. It is widely acknowledged that although opioids are effective at treating pain, their use leads to the development of severe adverse effects, such as constipation, addiction, and respiratory depression. Thus, there is a clear need for a safer alternative to manage pain. One such alternative is to enhance the effects of the body’s endogenous opioid system by positive allosteric modulation (PAM) of MOR. A PAM characterized in my thesis, BMS122, enhances MOR mediated effects in cellular models and MOR induced pain relief in mice. Additionally, BMS122 does not induce the adverse effects associated with opioid use. My thesis aims to characterize how BMS122 functions in cellular and animal models to combat the current challenges of traditional opioid use.

Shopping Behavior in Paper Wasps: Causes and Consequences of Social Group Formation
Emily Laub, Ecology and Evolutionary Biology

Cooperation is observed across animal taxa, yet how this behavior evolved has remained controversial. Assortment of specific cooperators has been theorized to play an important role in the evolution of cooperation. However, what traits make individuals “better” cooperators and how cooperators are evaluated remains understudied. Paper wasps provide an ideal opportunity to study the relationship between social group formation and cooperation as nest founding queens synchronously engaging in “shopping” for social partners at the beginning of the summer. In my dissertation research, I evaluate social group formation in paper wasps to examine what characteristics contribute to specific groups joined, how early social interactions shape group choices, how facial recognition contributes to social group formation, and how group choices may impact group and individual fitness outcomes. My research will forward our understanding of how cooperation evolves, and the role group formation may play in maintaining cooperative behavior.

Multi-Objective Engineering of Therapeutic Antibodies
Emily Makowski, Pharmaceutical Sciences

Despite the success of antibody therapeutics, there are several outstanding challenges related to antibody drug development that impede progress. First, it is challenging to generate informative datasets of antibody biophysical properties (e.g., self-association and non-specific binding), and, even if this data were available, it is also difficult to develop predictive models needed for antibody co-optimization. To address these challenges, I have first developed multiple high-throughput and ultra-dilute (<0.02 mg/mL antibody) experimental techniques for evaluating antibody colloidal interactions. I then have applied machine learning methods for the prediction of antibody affinity and colloidal properties that use conventional and novel (deep learning) molecular features. These models facilitate the selection of antibody candidates with co-optimal properties as well as the optimization of candidates with suboptimal properties. Additionally, I have developed methods for interpreting these models’ predictions using explainable artificial intelligence, elucidating structural motifs responsible for these properties providing insight for future therapeutic antibody development.

Investigating the Spatio-Temporal Patterns of Germline to Soma Communications During Germ Cell Differentiation, Meiosis, and Spermiogenesis
Gabriel Manske, Cellular and Molecular Biology

The male reproductive system is responsible for producing sperm, the highly specialized terminally differentiated cells which are essential for the survival of our species. Despite decades of research, we still do not fully understand the intrinsic and extrinsic programs necessary for sperm production. Particularly, we are missing how somatic cells communicate with germ cells to coordinate germ cell maturation over time. Our pioneering single-cell transcriptome sequencing experiments uncovered the complex programs which direct germ cell differentiation. However, this methodology does not identify the cellular context in which these programs are utilized. My thesis focuses on creating technologies to capture the spatial and temporal context of gene expression during spermatogenesis in order to provide insights into how somatic cells coordinate location-appropriate flow of information to multiple stages of germ cells. This work will identify novel targets for male contraception and improve our capability to reconstitute spermatogenesis in vitro.

Investigating the Role of Sleep in Neurodevelopment, Synaptic Plasticity, and Memory Processing
Jessy Martinez, Molecular, Cellular, and Developmental Biology

Sleep is thought to be a critical regulator for the refinement of neural circuitry during neurodevelopment. Under conditions where postnatal neurodevelopment is modified by altered sensory experience, or in the case of genetic mutation-induced neurodevelopmental disorders, sleep is commonly altered or disrupted. However, while sleep plays a role in promoting brain plasticity, it is unclear whether normalizing sleep could help normalize brain functions in atypical neurodevelopment. My thesis work addresses this gap by measuring how sleep loss affects recovery of disrupted visual cortex function in a mouse model of amblyopia (a developmental condition leading to vision loss) and testing how normalizing sleep behavior affects memory disruptions in a model of Fragile X syndrome (a genetic disorder). Through electrophysiological, behavioral, and molecular techniques, my studies suggest that sleep not only is critical for recovery mechanisms in disrupted neurodevelopment, but is a potential target for therapeutic intervention.

The Influence of Seasonal Migration on the Evolution of North American Birds
Teresa Pegan, Ecology and Evolutionary Biology

I study the evolutionary consequences of seasonal migration in birds. My dissertation explores two distinct ways in which seasonal migration may affect avian evolution. First, I use geographic, environmental, and genetic information to assess the consequences of migration for species’ geographic ranges and population connectivity. Second, I use life history and genetic information to understand how migration affects the balance between survival and reproduction, which influences rates of molecular evolution. I investigate these questions in a comparative context using the community of small bird species breeding in North America, with particular focus on species breeding in the boreal forest. My results are applicable to our understanding of avian evolution and global biodiversity more generally: Understanding the influence of climatic adaptation on evolution is critical to understanding variation in evolution across the globe, which leads to the striking patterns of biodiversity we see on our planet.

Targeting Corticospinal Pathways Via Operant Conditioning to Improve Quadriceps Strength and Function
Kazandra Rodriguez, Movement Science

It is theorized reduced corticospinal excitability contributes to quadriceps dysfunction after knee injury and joint disease. Current rehabilitation does not directly target the alterations in corticospinal excitability, which may limit recovery. Operant conditioning is an emerging approach capable of increasing corticospinal excitability by directly targeting the corticospinal pathways. However, it remains to be determined whether operant conditioning of the corticospinal pathway may improve quadriceps function after knee trauma. Further, dosage parameters used during operant conditioning (i.e., stimulus intensity and number of trials) appear to be selected arbitrarily and lack evidence supporting its superiority. Given the importance of appropriate dosage for intervention efficacy, use of sub-optimal parameters may limit therapeutic benefits. Therefore, this dissertation will: 1) evaluate the ability of operant up-conditioning of the corticospinal pathway to improve quadriceps function and 2) determine the effect of stimulus intensity and the number of training trials on the ability to increase corticospinal excitability.

Embeddedness and Environmental Governance of Supply Chains: A Study of Palm Oil
Calli VanderWilde, Environment and Sustainability

Palm oil demand has caused significant global deforestation, especially in Southeast Asia and, increasingly, Latin America. Certification has emerged as a major governance strategy to attenuate the commodity’s impacts on forests. This dissertation applies a mixed-methods approach to a case study of Guatemala—palm oil’s latest frontier—to assess whether certification has indeed improved environmental governance. It specifically investigates whether certification has fostered embeddedness and reduced forest loss. The study uses: transaction-level customs data and dynamic network analysis techniques to quantify the embeddedness of (un)certified supply chain actors; and, remote sensing and machine learning approaches to quantify impacts of (certified) palm oil plantations on forests in Guatemala. Land change and embeddedness outputs are combined to document whether actor embeddedness mediates deforestation occurrences. The mixed-methods approach, extendable to other commodities / supply chains, advances embeddedness theory while generating spatiotemporal evidence of gaps in palm oil supply chain sustainability and environmental governance.