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Committee:

William B. Klimstra (dissertation advisor)Joshua MattilaJohn AlcornCynthia McMillen

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Department of Human Genetics Doctoral Candidate, Caroline Ward, BA, will defend the following dissertation on “Integrated Imaging and Genetic Approaches to Elucidating Islet Heterogeneity in Health and Diabetes”

COMMITTEE CHAIR: Zachary Z. Freyberg, MD, PhD

Committee Members:

Beth L. Roman, PhDQuasar S. Padiath, PhD, MBBSMichael J. Jurczak, PhD

ABSTRACT:

The pancreatic islet is a heterogeneous micro-organ whose cellular composition and signaling vary across cell types, anatomical location, sex, and disease state. This dissertation develops complementary strategies to resolve that heterogeneity, first in human type 1 diabetes (T1D) and then in a mouse model of β-cell dopamine signaling.

In the first study, an AI-guided whole-slide imaging pipeline coupled to a hierarchical Bayesian and mixed-effects statistical framework was applied to immunohistochemically stained pancreata from 106 non-diabetic and T1D donors, quantifying all four endocrine cell types across more than two million islets. T1D produced a coordinated remodeling of islet composition: profound β-cell loss was accompanied by reciprocal α-cell expansion, whereas δ- and PP-cells were largely resilient. These changes were regionally concentrated, most pronounced in the pancreatic head, and were modulated by sex, age, and disease duration, with pseudotime analysis resolving distinct trajectories of compositional change across disease progression.

The second study examined the contributions of β-cell dopamine D2 receptor (D2R) signaling to glycemic control using a tamoxifen-inducible, β-cell-specific D2R conditional knockout (cKO) mouse model. Loss of β-cell D2R produced sex-dependent metabolic phenotypes: females showed blunted glucose-stimulated insulin secretion and diet-dependent glucose intolerance, whereas males showed enhanced glycemic control and islet secretion. Multiplex RNAscope revealed that islet D2R is expressed in a subpopulation of β-cells, suggesting that D2R may contribute to the emerging understanding of β-cell heterogeneity.

Taken together, both studies highlight important roles for sex differences in β-cell function. Just as importantly, this work uses complementary imaging, genetic, and physiologic approaches to define distinct populations of endocrine cell types, both under physiologic and disease contexts.

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Dissertation Committee

Brittany Brown-Podgorski, PhD, MPH, Department of Health Policy and Management, School of Public Health (Committee Chair)
Marian Jarlenski, PhD, MPH, Department of Health Policy and Management, School of Public Health
Tamar Krishnamurti, PhD, School of Medicine
Tina Batra Hershey, JD, MPH, Department of Health Policy and Management, School of Public Health
Victoria Bacon, MS, MPH, LCGC, UPMC Magee Women's Hospital, UPMC Presbyterian Hospital - Heart and Vascular Institute

Abstract
Prenatal genetic testing evaluates the presence of fetal genetic anomalies and is an essential part of evidence-based prenatal care. Prenatal genetic counselors (GCs) often facilitate testing and care delivery, allowing pregnant people to make decisions about their current and future pregnancies. Though prenatal genetic testing is recommended during prenatal care, it is costly and often inaccessible to low-resourced and uninsured pregnant people.

Medicaid coverage improves access to prenatal genetic services for low-income pregnant people, which may affect infant health outcomes. However, Medicaid coverage often varies across jurisdictions, and access to genetic services may be complicated by reproductive health policy changes following Dobbs v Jackson Women’s Health Organization (2022). This dissertation utilizes a multiple methods approach to better understand the policy landscape for prenatal genetic services and how it influences care delivery and infant health outcomes.

Aim 1 uses a rigorous legal mapping technique to characterize Medicaid coverage for non-invasive prenatal testing (NIPT), amniocentesis, and chorionic villus sampling in 51 United States jurisdictions as of 2025. We redundantly coded state-level policies, noting policy sources, effective dates, eligibility criteria, covered conditions, and prior authorization requirements.

Aim 2 uses national Pregnancy Risk Assessment Monitoring System data between 2011 and 2022 and a two-way fixed effects difference-in-differences analysis to estimate the impact of state Medicaid coverage for NIPT on birth defects. Our treatment group included those in states with NIPT coverage and information on birth defects. Our control group included those in states without NIPT coverage during our study. We controlled for individual-level and state-level factors affecting exposure to the policy and outcome.

Aim 3 consists of semi-structured interviews to understand how prenatal GCs operationalize practice-based competencies from their training in varying state policy environments. The interview guide included questions about day-to-day practice, a patient vignette, and if abortion policies affect care delivery. Interview transcripts were analyzed using deductive and inductive coding.

Our findings suggest that the policy environment affects prenatal genetic care delivery and infant health outcomes. This highlights the important role of policy in facilitating access to genetic services and underscores the potential implications of recent Medicaid and reproductive health policy changes.

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Department of Human Genetics Doctoral Candidate, Kimiasadat Golestaneh, BS, will defend the following dissertation on “Deciphering the Role of SOX2 During Retinal Development”

COMMITTEE CHAIR: Issam Al Diri, PhD

Committee Members:

F. Yesim Demirci, MDSusana da Silva, PhDBeth L. Roman, PhD

ABSTRACT:

Retinogenesis requires precise synchronization of progenitor cell competence, spatial patterning, and cell fate specification. Retinal progenitor cells give rise to all retinal cell types in a highly ordered spatiotemporal manner. However, little is known about the gene regulatory mechanisms that maintain progenitor competence within retinogenesis. SOX2 is a key transcription factor expressed in retinal progenitor cells, a subset of amacrine cells, and Müller glia, and it is essential for neural competence. Mutations in SOX2 are associated with human eye developmental abnormalities, including microphthalmia and anophthalmia, underscoring its significance in eye development. However, the mechanisms by which SOX2 regulates retinal progenitor identity, patterning, and differentiation remain poorly defined.

I investigate the role of SOX2 during retinal development, focusing on how SOX2 regulates retinal progenitor cell identity, spatial tissue organization, and the transition from progenitor states to differentiated retinal cell types. This work investigates the effect of Sox2 loss in the developing retina and identifies regulatory changes associated with neural competence, spatial identity, and retinal cell fate specification by using genetic, molecular, transcriptomic, and chromatin accessibility approaches.

The findings show that SOX2 is required to sustain retinal progenitor cell identity and to support gene regulatory networks essential for retinal development and patterning. Loss of Sox2 disrupts progenitor identity by shifting the balance between progenitor maintenance and cell fate progression, altering retinal patterning, and affecting cell cycle progression. This work further identifies SOX2 as a key regulator of the boundary between the neurogenic neural retina and the non-neurogenic ciliary margin. Although this boundary is disrupted upon Sox2 loss, the core dorsoventral organization of the neural retina remains intact, suggesting that developmental competence and spatial patterning are controlled by partially separable regulatory programs. Overall, this dissertation identifies SOX2 as a central regulator of enhancer accessibility, neural retinal identity, progenitor competence, and spatial tissue organization during retinogenesis.

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Committee:

Joshua T. Mattila (chair)Allison KohanBerthony DeslouchesJeremy Martinson

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Join the Mascaro Center for Sustainable Innovation, the Office of Sustainability in the Health Sciences, and the School of Public Health for a keynote conversation with author Andrew Moore and a panel discussion exploring the connections between One Health, Planetary Health, and Sustainability. Networking and refreshments to follow.

Keynote:

Andrew More, author of The Beasts of the East: The Fall and Rise of America's Eastern Wilderness

Panel Moderator:

Melissa Bilec, PhD, George M. and Eva M. Bevier Endowed Chair, Professor in Civil and Environmental Engineering, and Co-Director of MCSI

Panelists:

Maureen Lichtveld, MD, MPH, Dean of the School of Public Health, Professor of Environmental and Occupational Health, Jonas Salk Chair in Population Health

Cori Richards-Zawacki, PhD, Professor in Biological Sciences and Director of the Pymatuning Lab of Ecology

Noe Woods, MD, Assistant Professor of OB/Gyn at the School of Medicine and Chair of the Clinicians for Climate Action

Please save the date for this event - more details and registration link coming soon!

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Panelists: TBA

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