University Of Rochester

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Cyclic AMP (cAMP) is a critical secondary messenger that modulates many cell signaling pathways throughout physiology. Adenylyl cyclase (AC) catalytically converts ATP to cAMP in response to G protein- coupled receptor signaling, thus acting as an essential relay and integration center for cell signaling. Currently, ACs represent an unexploited target for treating a range of diseases including cancer, chronic obstructive pulmonary disease, neuropsychiatric disorders, diabetes, heart disease, and drug abuse. Within a cellular context, differential expression, compartmentalization, and microdomain localization of nine transmembrane AC isoforms give rise to a broad range of possible signaling outcomes, complicating our ability to therapeutically target this critical rheostat of cell signaling. Our mechanistic understanding of AC function is limited, with only a recent first glimpse of a full-length AC-Gαs structure revealed by cryo-electron microscopy (cryoEM). However, the static snapshot of AC in isolation forms an incomplete picture of the spatiotemporal signaling that occurs in vivo. The lack of molecular and mechanistic details of AC signaling assemblies in native environments leaves a gap in our understanding, further restricting the development of pharmaceuticals targeting AC and cAMP pathways. To address this gap, the overarching goal of this proposal is to capture physiologically relevant complexes between adenylyl cyclase and signaling partners in near-native and cellular environments. This will be achieved through the following specific aims: (1) structurally and biochemically characterize a functional signaling assembly of adenylyl cyclase, and (2) visualize adenylyl cyclase microdomain topography and its dynamics in response to cyclase activation in situ. Completing these aims will represent a substantial leap forward in adenylyl cyclase biology, providing the framework for further adenylyl cyclase study. This work builds upon my G protein biochemistry background and experience with cell signaling assays, protein purification, and fluorescence microscopy. Taking advantage of the world-class training and resources available in the laboratory of my mentor, Dr. Georgios Skiniotis, the proposed studies also provide an opportunity to acquire expertise in structural biology, cryo-electron tomography, proteomic approaches, sharpen my abilities as a researcher, and develop as an emerging leader in the adenylyl cyclase field. As a result, I will be well-positioned to establish a program of successfully funded independent research.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The objective of this application is to furnish investigators from the University of Rochester, University of Rochester Medical Center (URMC), and their collaborators with a state-of-the-art small animal imaging system, the Vevo F2 LAZR-X. This advanced instrument, known as a high-resolution multi-model Ultrasound and Photoacoustic Imaging System, offers the essential tools and resources to propel their interdisciplinary research forward. With its ability to conduct real-time in-vivo imaging in rodents, the system can also be used to study large animals. The University of Rochester boasts a robust portfolio of NIH-funded research programs and is the hub for a large group of NIH-funded investigators conducting pioneering studies and translational research across diverse research areas. These investigators represent many distinct departments associated with five core research centers or institutes, guided by a nationally recognized research team specializing in ultrasound and photoacoustic imaging. Currently, despite a significant research demand for access to small animal imaging facilities, the University of Rochester and URMC lacks a state-of-the-art photoacoustic imaging system for detailed anatomical, functional, physiological, and molecular imaging. The aim of this application is to procure the Vevo F2 LAZR-X ultrasound and photoacoustic imaging system that will enable investigators to undertake a wide spectrum of foundational and applied research projects. The principal investigator and the key contributors seek not just enhancement of new and ongoing research programs, but also to achieve greater understanding and appreciation of the underpinning science and technology. Introducing this distinctive and state of the art equipment to the University of Rochester will foster collaboration among researchers who bring complementary methodologies to the table. This will bolster advancements in both scientific and technological domains and enhance the development of our human resources. Acquiring and maintaining state-of-the-art imaging methodologies attracts the best and brightest, produces sought-after trainees with cutting edge training and marketable skills, and fosters the continuing success of our NIH-funded programs across multiple disciplines.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract: The AAALAC, International accredited, University of Rochester requests this Equipment Grant funding to purchase a bulk, Gruenberg™ Dry Heat Sterilizer to double sterile mouse cage throughput to meet growing program needs as well as to reduce labor and utilities expenses. All mouse caging is sterilized before each use. Ultrafiltered (0.1 micron), municipal water is provided by the Hydropac™ system. Two separate, vivaria, Kornberg Medical Research Building KMRB (23,273 sq ft) and School of Medicine & Dentistry SMD (53,861 sq ft) each house approximately 9,000 autoclaved cages of SPF mice on HEPA-filtered, ventilated racks. The KMRB, built in 1999, modernized and doubled the University's mouse-based, research capacity by designing efficient use of suites adjacent to a modern cagewash and housing mice in seventy-five, labor-saving, HEPA-filtered, ventilated racks. The high throughput bulk, steam autoclave and tunnel washer in the KMRB met the needs of the new SPF mouse facility with intentional excess capacity for expansion into adjacent shell space. The SMD vivarium, built in 1965, originally met the needs of over 300 conventionally housed dogs, 150 macaques, 60 cats, 200 rabbits and 1 0 rooms of conventional rodents housed on 7 floors in the SMD. The original SMD cagewash design included three passthrough cage/rack washers in the wall between two equally sized, soiled and clean sides. Over time, the SMD large animal census has declined to less than 30 macaques, 7 rabbits and no dogs or cats. In contrast, the SPF mouse census in the SMD has increased to over 9,000 cages all housed in HEPA-filtered, ventilated racks. The SMD Vivarium supports 98 principal investigators across 38 departments. A total of $277M funded mouse-based research ($184M NIH, $33M Institutional, $23M Corporation, $15M Foundation, $1 OM DOD, $12M Other) depends on the outdated SMD vivarium cage wash. SMD cage wash facility currently includes one cage/rack washer and two, small chamber autoclaves. In January 2024, we achieved a first step to modernize the SMD cage wash facility for mice by replacing one of the two rack washers with a Vivus Technologies™ tunnel washer. While the new tunnel washer has significantly advanced more efficient mouse cage washing, the cabinet autoclaves continue to pose a bottle neck with low through-put. If awarded this $350,000 equipment grant, the university has committed an additional $57,000 for the purchase of the $407,000 Gruenberg™ Dry Heat Sterilizer (Model VST40H280.OSS-2D-RM-G) plus an additional $207,000 to prepare a level, heat resistant floor and bring the necessary electrical, exhaust and compressed air utilities to the installation site. Addition of the Gruenberg™ Dry Heat Sterilizer will reduce labor and utilities expenses for SM D's current 10,000 cage census as well as position the university for meeting the needs of new recruits even with a doubling of the mouse cage census.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The mucopolysaccharidosis (MPS) disorders are a set of heterogeneous progressive, life-limiting disorders with variable multi-system complications, including highly diverse effects on the central nervous system (CNS), ranging from rapid neurocognitive decline, often with intense behavioral dysregulation, to mild memory issues. While there has been an explosion in therapy development for MPSes, the ability to measure a convincing response to therapy is complicated by the variable clinical courses across, and within, phenotypes. Incredibly divergent clinical trial approaches internationally had hindered data comparison and raised questions as to whether methodologies were accurately measuring cognitive and adaptive endpoints. In response, two prior international MPS consensus conferences developed guidance for MPS trial design and implementation, particularly for therapies targeting CNS effects. Given rapid advances in the past four years in knowledge about treatments, disease pathology, and the patient/family experience of MPS disorders, it is critical to update the guidance to keep pace with this surging field. The main objective of the Third Consensus Meeting on Neurocognitive and Functional Endpoints in MPS Clinical Studies is to launch a Delphi consensus process to modernize guidance for MPS clinical studies targeting both the CNS and multi-functional impacts of the disorders. The specific aims are to: 1) Update recommendations for endpoint measurement of CNS impacts of MPS across the globe; 2) Improve representation of the diverse needs of MPS disorders, broadening the set of endpoints to be meaningful for how patients/families feel and function; 3) Mentor trainees/early stage investigators (ESIs) on (i) identifying issues in neurocognitive and other functional endpoints and clinical trial execution, (ii) writing literature review talks for the conference, and (iii) composing a manuscript for peer review. A 2-day, in person meeting with a diverse MPS expert panel (researchers, clinicians, advocates) and mentored participation by trainees/ESIs will develop statements for a virtual Delphi process. The proposal's significance is its emphasis on diversity and global representation of a broader set of functional endpoints for MPS clinical studies. Major outcomes of this conference will be to develop modern recommendations for selection and implementation of endpoints that are clinically meaningful to patients/families across the globe, and to enhance career development for trainees/ESIs. This proposal's health relatedness is its potential to guide investigators and industry in trial designs that reliably evaluate CNS response to therapy. The ultimate goal is to accelerate the success of clinical programs for new therapies, and inclusive treatment targets, to improve the lived experience of people touched by MPS.

NIH Research Projects · FY 2025 · 2025-08

Project Summary In addition to the ethical considerations of using animals for biomedical research, the high costs, low throughput, and limited translation of mice motivates their reduction and replacement with human tissue-on-chip (hTOC) for disease modeling, drug development, and discovery. One frontier in hTOC development is the modeling of aging as a confounding factor in disease. Our focus is on the blood-brain barrier (BBB), which is known to become less robust at regulating the passage of cells and molecules from blood as people age. Age- related changes in the BBB include cellular and transport changes that make the brain more vulnerable to injurious circulating factors and neurodegeneration. This includes impairment of lipoprotein receptor related protein-1(LRP-1), which leads to amyloid beta (Ab) accumulation in the brain, a hallmark of Alzheimer’s disease (AD). In addition, the presence of the Apoe4 allele, a risk factor for AD, accelerates most of the aging related changes in the BBB. Traditional animal models of AD and the BBB lack human relevance. Importantly, the mouse does not naturally develop human neurodegenerative diseases, including AD, and must be genetically engineered to approximate the condition. In animals that do naturally develop AD or cognitive decline such as non-human- primates or canines, the age-of-onset is too long for practical progress. For these reasons we will combine induced-pluripotent stem cell (iPSC) and microphysiolocial systems technologies with small molecule ‘aging’ cocktails to develop the first hTOC aged model of the blood brain barrier: the µSiM-aBBB (microphysiological system enabled by a silicon membrane-aged BBB). We will model geriatric vulnerabilities to genetic predisposition of the Apoe4 allele in the BBB by mirroring the cellular changes that occur during aging having shown preliminary induction of senescence, shifts in protein expression and increases in barrier permeability in our aged model. Thus, I hypothesize that consistent with the onset of AD occurring in older patients homozygous for Apoe4, aged cellular phenotypes combined with the Apoe4 mutation produce a BBB that is intrinsically compromised compared to Apoe4 or aging alone. To test this hypothesis, I will pursue two aims. Aim 1 will establish and characterize our model, the µSiM-aBBB using colorimetric assays, immunohistochemistry, permeability assays and ELISAs. Aim 2 will determine how the presence of the genetic risk factor, Apoe4, combined with aging affects barrier integrity and function in the BBB using RNA sequencing as well as the methods mentioned in aim 1. The proposed experiments will create a novel tool that can be used to determine ways to prevent barrier dysfunction under compromised conditions. This project will demonstrate the value of hTOC models to emulate human health and disease and expand our knowledge on the combined effect of genetics and aging on the human BBB.

NIH Research Projects · FY 2025 · 2025-08

Pancreatic ductal adenocarcinoma (PDAC) owns the ominous ranking as the most lethal malignancy of all major cancers. These dismal survival rates can be largely attributed to specific intrinsic and extrinsic barriers that foster metastatic dissemination and impart treatment resistance. Our group and others have demonstrated that epithelial to mesenchymal transition (EMT), a cellular program intrinsic to tumor cells, promotes metastases and is a major barrier to treatment efficacy. However, an additional extrinsic barrier exists, notably a signature immunosuppressive tumor microenvironment (TME) that not only inhibits most anticancer therapies, but also exacerbates the progression of EMT. This proposal will test the overarching hypothesis that both barriers must be targeted in order to develop an effective therapy against metastatic PDAC. To accomplish this, our laboratories have investigated an alternative treatment strategy that administers a therapy directly to the TME consisting of local radiotherapy and intratumoral immunotherapy. This innovative approach would concentrate the therapeutic payload to the tumor specifically, which we hypothesized could overcome the immunosuppressive properties of the PDAC TME. To test this, a novel nanotechnology was generated where a modified monomeric mRNA sequence of the potent immunostimulatory cytokine interleukin-12 (IL12) was encapsulated in a lipid nanoparticle (LNP) specifically designed to maximize intratumoral uptake and endosomal release of the ribonucleic acid when administered directly to the TME. This immunotherapeutic was combined with localized stereotactic body radiotherapy (SBRT); an emerging radiotherapeutic for the treatment of PDAC, which augments the efficacy of immunotherapy. The treatment schedule of SBRT (6Gy/day over 4 consecutive days) followed by an intratumoral injection of IL12mRNA resulted in remarkable tumor elimination and long-term survival in multiple preclinical models of PDAC. The success of this local combinatorial approach was attributed to a profound repolarization of the PDAC TME that was now capable of supporting potent antitumor T cell responses. However, we discovered that although SBRT/IL12mRNA was effective in eliminating metastatic disease in 70% of mice, 30% of the tumors experienced treatment resistance due to tumor cell mesenchymal transition. These results suggest that reversing tumor cell EMT will maximize SBRT/IL12mRNA efficacy and overcome both extrinsic and intrinsic barriers to effective systemic therapy. Aim I will investigate CD4 T cells; a subset of antitumor effector cells generated in response to SBRT/IL12mRNA treatment, which we hypothesize are essential to “condition” distal metastases, mediating systemic immunity. Aim II will test a novel therapeutic targeting Netrin-1 (NP137), a potent inducer of EMT in PDAC tumor cells, and determine how inhibiting mesenchymal transition overcomes treatment resistance to SBRT/IL12mRNA therapy. This proposal will guide the development of a new generation of therapies that emphasize both the repolarization of arduous TMEs (an extrinsic factor), but also the reversal of the mesenchymal phenotype intrinsic to the PDAC tumor cell.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Breast cancer is the most widely diagnosed cancer in women in the United States and the most commonly occurring cancer worldwide according to the World Health Organization. The primary screening method for non- palpable breast cancers is X-ray mammography, which uses ionizing radiation and often has low sensitivity and specificity in dense breast tissue. Ultrasound tomography (UST) offers a radiation- and compression-free alternative to X-ray mammography that can image the breast based on its acoustic properties and enable early cancer detection and diagnosis with greater sensitivity and specificity, especially in dense breast tissue. Currently, UST imaging of the breast relies on the transmission of ultrasound through the tissue to reconstruct underlying tissue properties such as sound speed and attenuation. However, the full-waveform inversion (FWI) algorithm used to reconstruct these tissue properties is susceptible to false local minima because of a nonconvexity in FWI known as cycle skipping. Additionally, the slicewise imaging approach currently used in UST limits the ability to correct for 3D out-of-plane scattering. Finally, because FWI reconstruction in UST is primarily based on the transmission of ultrasound through tissue, little attention has been given to exploiting reflected signals during FWI. Each of these shortcomings prevents FWI from adequately modeling high- frequency signals, ultimately limiting the currently achievable imaging resolution of UST. Therefore, this work proposes to enable high-resolution UST imaging by (1) mitigating cycle skipping effects, (2) capturing the 3D insonification of the tissue, and (3) incorporating reflected signals into FWI. In order to expand the capabilities of UST imaging, I aim to: overcome cycle-skipping effects that limit the usability of high-frequency signals in UST by reformulating FWI (Aim 1); design and build a UST imaging prototype that can optimally capture and utilize the 3D insonification of the tissue to reconstruct sound speed and attenuation with greater accuracy and resolution (Aim 2); and incorporate reflected signals into FWI to recover sharp boundaries in the sound speed image caused by impedance changes in the tissue (Aim 3). These aims will improve the scientific understanding of acoustic models applicable to ultrasound signals in both transmission and reflection, as well as how these models may be inverted to reconstruct accurate and spatially resolved images of tissue properties. Expanding the tissue characterization capabilities of ultrasound tomography will enable a multi-parametric approach for the detection and characterization of breast cancer using an imaging modality without ionizing radiation. Improving the robustness of UST in acoustically challenging cases will also enable new imaging applications such as small-animal and human-transcranial imaging. The proposed work will also broadly benefit the field of ultrasound imaging by improving tissue modeling and characterization capabilities and enabling the early detection of disease based on acoustic tissue properties.

NIH Research Projects · FY 2025 · 2025-07

Human Cytomegalovirus (HCMV) causes substantial disease in immunosuppressed patients, including hematological cancer patients and transplant recipients. Further, HCMV is a major cause of congenital disability. Successful HCMV infection relies on the viral modulation of many cellular factors. To identify novel cellular determinants of HCMV infection, we have performed targeted CRISPR screens of biochemical data sets and identified JUNB as a cellular factor that can inhibit HCMV infection. JUNB is a stress-induced transcription factor that regulates inflammation. Our data suggests that the HCMV UL26 protein binds JUNB, thereby attenuating its anti-viral activity. We will identify the mechanisms through which JUNB can restrict HCMV infection (Aim 1) and elucidate how JUNB induces the activation of inflammatory gene expression (Aim 2). Lastly, we will determine how UL26 modulates JUNB’s activity (Aim 3). Collectively, our proposed research will explore how a key inhibitor of anti-viral responses, UL26, modulates the activity of an important regulator of inflammation, JUNB. The mechanisms involved will further our understanding of important host-pathogen interactions and could potentially pave the way for novel therapeutic interventions.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT The lung, as it is constantly challenged, has a unique immune system, much of which is still underappreciated. Respiratory viral infection, including influenza and SARS-CoV-2, is among the worst burdens of disease worldwide and in the US, and especially viral pneumonia is one of the leading causes for irreversible tissue damage and death. Importantly, immune responses of the lung to the viral infection determine the outcome of these viral illnesses, so better understanding of the lung immunology is warranted. CD8+ T cells are the most important immune effector against viral infection of the respiratory organs because they significantly reduce virus burden and spread by eliminating infected cells. But T cell immunity is not an autonomous system and innate immune cells are required for the T cells to be functional. In the lung, dendritic cells (DCs) and macrophages play such regulatory roles in general. I had previously demonstrated that tissue- infiltrated monocytes are also important for efficient T cell immune responses during influenza infection of the lung and trachea, adding to the knowledge of innate immune regulation of T cell responses. Now I have strong evidence that the monocytes infiltrating into the lung during influenza virus infection further differentiate into a novel myeloid cell type, long-lived highly differentiated monocyte-derived cell (LDM), and the LDM cells persist in the lung for many months since recovery from the infection. I also obtained preliminary, but significant, data indicating that those LDM cells are a key regulator of lung-resident memory T cell (TRM). TRM is an effective cytolytic immune effector to protect hosts from recurrent infection, however current understanding of regulatory mechanisms for lung-resident T cell memory remains insufficient. We will address an unsolved issue in this field–how lung TRM is regulated by innate immunity. In Aim 1, it will be tested if LDM, not conventional DCs, activates lung TRM upon recurrent influenza infection using a LDM depletion mouse model that I newly developed. In Aim 2, I will investigate the mechanism(s) by which the LDM activates TRM. Through rechallenge of virus-immune mice with viral antigens, reconstituted in vitro cell assays and reporter assays that distinguish cytokine signals and TCR activation signal, it will be determined if the LDM is a lung-resident antigen presenting cell (APC) type for TRM activation. In Aim 3, to corroborate evidence that the LDM promotes TRM activation, interaction, migration and tissue localization of LDM and TRM in the lung will be investigated using cutting-edge lung imaging technologies.

NIH Research Projects · FY 2025 · 2025-07

Summary: This application proposes to establish the Upstate NY Nathan Shock Center of Excellence in Basic Biology of Aging (Upstate NSC) focused on Comparative Biology of Aging. Comparative biology approach has a great potential to bring breakthroughs in the studies of aging and longevity. Lifespans range more than 100- fold between animal species. To generate this diversity of lifespans evolution has tested more longevity mechanisms than could be achieved in any laboratory experiment. These mechanisms are waiting to be revealed by applying comparative biology approaches. A major hurdle to broader implementation of comparative biology approach is access to resources and organisms outside of the conventional laboratory bestiary. Upstate NSC will fill this gap in resource and technology availability. Upstate NSC will combine the expertise of University of Rochester and Cornell University researchers, who have developed innovative and unique resources that can advance the field of aging biology. The proposed Research Resource Cores take advantage of this expertise to provide investigators across the nation with access to unique model organisms and state-of-the-art technology: We are proposing four Research Resource Cores that will seamlessly integrate to generate data and resources in Comparative Biology of Aging. (1) The Live Animal Core will maintain and share naked mole rats as a model of health aging, Damaraland mole rats as a short-lived sister species to naked mole rats, African Spiny mice as a model of regeneration and horses as a model of reproductive aging and miscarriage (2) The Unconventional Invertebrate Core will focus on eusocial ants and wasps where lifespans in individuals of the same species differ dramatically and can be manipulated by a parasite. The Live animal and Invertebrate cores will provide advice on experimental design and husbandry, protocols, specimens, and share live animals to assist investigators in establishing colonies at their institutions. (3) The Frozen Zoo Core will maintain collections of tissues from 50+ species of mammals and the species maintained by the above Cores. (4) The Comparative Omics Core will process samples from the first three Cores and develop novel technologies of high interest to aging research such as analyses of protein modifications and proteostasis, untargeted metabolomics, and unique processes of data integration across Omics platforms. The research cores will work together with the Research Development and Administrative/program enrichment cores to attract new talent and expertise to and distribute the resources to the community, making the Center as a whole greater than the individual parts. The Administrative Core will coordinate conferences, symposia, workshops, and seminars on aging biology. Upstate NSC will work closely with other funded NSCs and the aging community at large to develop collaborative projects and organize joint conferences. Upstate NSC will provide conceptual leadership and serve as a hub for the development and exchange of ideas that will inspire students, attract new investigators, and inform the public. Combining these activities in one integrated Center will effectively move the field of aging biology forward.

NSF Awards · FY 2025 · 2025-07

This Pathways to Enable Open-Source Ecosystems (POSE) project advances the ability to understand and predict global-scale geophysical, planetary, and solar phenomena, including ocean and atmospheric circulation. The project develops the FlowSieve codebase into an easily accessible open-source software ecosystem for probing fluid flows across scales on Earth and other planets, from local weather events to global circulation patterns. By providing these advanced computational tools in a publicly shared framework, this project transforms research in earth and planetary science, solar physics, and related areas. Improved understanding and prediction of these phenomena is essential for economic growth and public safety, including navigation and shipping, energy and resource management, and disaster resilience. Through community-driven development and maintenance, the project improves scientific and technological progress and promotes broad access to cutting-edge computational methods. The resource spurs discoveries benefiting researchers, educators, and policy makers. FlowSieve is a unique open-source codebase that implements a novel coarse-graining methodology for generating geographic maps of dynamical processes at different spatio-temporal scales in spherical domains, including oceanic and atmospheric flows within the earth system and flows on other planets. The codebase has been used for the analysis of data from global and regional models, and data from satellites and spacecrafts. This project helps to transform FlowSieve into an Open-Source Ecosystem (OSE). The OSE's main mission is to catalyze research in geoscience, planetary science, and beyond, by maintaining and evolving the platform to meet the needs of researchers in a decentralized manner following an open, asynchronous, and distributed development model. This POSE project pursues a multi-pronged effort to encourage and guide future users and developers within the broad geo- and planetary science communities. This guidance includes organizing tutorial sessions at major conferences, hosting a hackathon, assembling a comprehensive user manual, creating online tutorials, expanding test cases, and implementing automated testing. Another major goal of this POSE project is to draft a strategy and organizational structure toward transforming FlowSieve into a self-sustaining OSE with the aid of an external advisory committee. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY The tensile-bearing Achilles tendon is highly prone to acute- or overuse-induced injuries that lead to chronic tendon degeneration and heterotopic ossification (HO) called tendinopathy. Achilles tendinopathy is often associated with pain and disability with high socio-economic costs. The current standard of care for treating Achilles tendinopathy does not result in effective long-term functional recovery, although it provides short-term pain relief. The pathogenetic mechanisms of Achilles tendinopathy are largely unknown. Identification of early mediators in tendon in response to injury and elucidation of the cellular and molecular mechanisms underlying the pathogenesis of this disease will facilitate the development of new therapeutic strategies. Using novel transgenic mouse models with CaV1.2 wildtype or a gain-of-function mutant, we observed potent regulatory effects of increased Ca2+ influx through CaV1.2 on the development of Achilles tendinopathy with chondrocyte/osteoblast differentiation and ectopic bone formation. Using a reporter mouse line, our recent study found that expression of the CaV1.2 channel in tendon fibroblasts is robust during development but very restricted in adult Achilles tendons. In contrast, our preliminary data show substantial upregulation of Cav1.2 expression in response to cytokine injection (TNF-α or IL-1β) or Achilles partial transection, an injury that induces Achilles tendinopathy in wildtype mice. Substantial CaV1.2 channel expression is also observed in human diseased Achilles tendon by immunohistochemistry analysis. These new findings provide a rational linkage between high CaV1.2 expression and Achilles tendinopathy. Our population health studies of the TriNetX database further provide clinical evidence suggesting that aberrant CaV1.2 expression/activity is a potential molecular mechanism underlying Achilles tendinopathy. Therefore, we propose to test the overall hypothesis that increased Ca2+ influx through CaV1.2 acts as an early pathological mediator of Achilles tendinopathy; decrease of Ca2+ influx through CaV1.2 with L-type Ca2+ channel blockers (CCBs), conditional ablation of CaV1.2 or targeting a Ca2+-dependent signaling cascade downstream of CaV1.2 in tendon cells will ameliorate Achilles tendinopathy. To test this hypothesis, we propose three Specific Aims. In Aim 1, we will identify the tendon-specific role of Ca2+ signaling through CaV1.2 in regulating endochondral differentiation in tendon during AT development. In Aim 2, we will investigate CaV1.2 expression, the Ca2+ response and calcineurin activation in Achilles tendon in response to inflammation and mechanical stimulation. In Aim 3, we will evaluate the ability of L-type CCBs as a pharmacologic treatment to prevent and ameliorate Achilles tendinopathy in mice. We propose to fully characterize CaV1.2 gain-of-function and loss-of-function mouse models, the CaV1.2 reporter mouse line, the injury-induced mouse model, and surgically excised tendinopathy Achilles tissues from patients together with Ca2+ imaging and pharmacological approaches to address these aims. The findings of this proposal could provide a scientific rationale for repurposing the use of FDA-approved generic L-type CCBs to alleviate or treat Achilles tendinopathy.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY BST2/Tetherin is a key factor of the cellular intrinsic immune response that broadly restricts enveloped viruses. BST2 tethers nascent virions to the cell surface by embedding itself into cellular and viral membranes. Tethering not only limits viral release, but also facilitates adaptive immune recognition of the infecting virus. Tethered virions are opsonized by antibodies, which can be recognized by Fc receptors on both natural killer cells and macrophages, activating their ability to kill or phagocytose the infected cell. We have recently reported that SARS-CoV-2 is susceptible to BST2 restriction. However, the virus has evolved to use its Spike to downregulate BST2. Downregulation is achieved by an interaction between Spike and the extracellular domains of BST2, routing BST2 for lysosomal degradation in a Clathrin- and Ubiquitin-dependent manner. Remarkably, newly emerged variants of concern (VOC) have enhanced their ability to counteract BST2, suggesting that BST2 antagonism is a contributing factor to the host adaptation of SARS-CoV-2. Therefore, my long-term goal is to block the ability of SARS-CoV-2 to evade BST2 restriction. My overall objective is to understand the mechanism and implications of BST2 evasion by SARS-CoV-2. My central hypothesis is that mutations accumulated in the Spike of SARS-CoV-2 allow for more efficient counteraction of BST2, increasing virion release and reducing the susceptibility of SARS-CoV-2 to BST2-dependent antibody-mediated cellular responses. I will achieve my overall objective by exploring these two specific aims: (1) elucidate the mechanism of enhancement of BST2 antagonism across VOC, and (2) identify the driving pressures of BST2 antagonism. This work is significant as it will (1) fill the critical gap in knowledge of how SARS-CoV-2 evades BST2 restriction, and how VOC enhance this activity; (2) define the extent to which evasion of BST2 allows for evasion of antibody-mediated responses, and how this translates to vaccine efficacy; and (3) provide proof-of-concept for the design of antivirals to disable SARS-CoV- 2 antagonism of BST2 with the goal of both blocking viral replication and enhancing clearance of infected cells. The support provided by this F31 award will enhance my education by (1) facilitating my training in Surface Plasmon Resonance by Dr. Jermaine Jenkins and the URMC Structural Biology Core Facility (see letter of support), (2) allowing me to travel to the University of Wisconsin-Madison to gain hands-on training from my co- sponsor, Dr. David Evans (see co-sponsor statement), who developed assays to measure Fc receptor-mediated killing of infected cells, which we are proposing to use here, and (3) expanding my experience in scientific writing and communication as I publish my findings and present at both national and international conferences.

NIH Research Projects · FY 2025 · 2025-07

Pneumocystis pneumonia (PCP) remains a serious life-threatening respiratory fungal infection of immunocompromised patients, and one of the most common AIDS-defining illnesses in the US and the world. PCP-related mortality rates have changed little over the past two decades, likely due to our inability to adequately treat the infection without exacerbating immunopathogenesis. Adjunctive corticosteroids are used to suppress inflammatory injury during antibiotic treatment, but the benefit of these broadly acting agents is uncertain. The mechanisms by which Pneumocystis (PC) is recognized and cleared from the lung remain incompletely understood. Alveolar macrophages (AMs) are important effectors of pulmonary innate immunity, but they are typically ineffective for host defense against Pneumocystis when CD4+ T cell help is not fully functional. The reason for this is unknown, but it has been suggested that PC actively evades or suppresses macrophage mediated host defense to ensure survival and transmission. Our laboratory has identified an inbred mouse strain which is unique in that it displays robust and rapid innate immunity against PC in the absence of CD4+ T cell function. The resistant phenotype requires AM-dependent removal of PC, but the specific mechanism remains unknown. In vitro studies have failed to reveal distinct differences in the phagocytic potential of resistant and susceptible AMs, leading us to hypothesize that the lung environment and lung epithelial cells (LECs) are critical components of effective innate immunity against PC. To test this hypothesis, we will utilize the resistant and susceptible mouse models described in our preliminary studies. Our long-term goal is to identify the effector mechanisms responsible for FVB protective innate immunity. We predict that the robust and rapid removal of PC from the lungs of FVB mice suggests that once identified, this mechanism might be exploited to design novel strategies that quickly eradicate PC without eliciting immunopathogenesis, providing improved outcomes in HIV and other patients with compromised CD4+ T cell function. In order to advance this goal, we propose two Specific Aims that will: 1) define the early transcriptional profiles of resistant (FVB) and susceptible (Balbc) LECs following the in vivo interaction with PC; and 2) directly determine whether the FVB lung environment, including LECs, is required for effective innate immunity against PC. If the proposed hypothesis is correct, these studies could drive new directions of research into the mechanisms that regulate pulmonary innate immunity.F2

NSF Awards · FY 2025 · 2025-07

This project aims to serve the national interest by improving curricula in computer science education. Computing professionals need to understand the possibilities and limitations of computation in order to design efficient algorithms for problems that can be solved in practice, or to avoid large investments in attempts to implement solutions for problems which have been proven to require unreasonable amounts of time or other resources. Modeling computation is an important building block for this understanding, however, students often struggle with abstract modeling and visualization. A prior Level 1 Engaged Student Learning project resulted in a prototype tool which provides immediate feedback on the computational models designed by students. This Level 2 Engaged Student Learning project aims to add features to the tool, improve its usability and adaptability, and investigate its impact on student problem-solving at a larger scale, in different educational settings. The existing Automated Feedback for Computing Theory (AFCT) prototype tool was built on the widely used Java Formal Languages and Automata Package (JFLAP) visualization tool that aids students in learning the basic concepts of formal languages and automata theory. The enhanced tool developed in this project will initially be deployed and outcomes assessed in theoretical computer science courses at the five collaborating institutions. It will be made available under an opensource license to enable others to use and modify the software to suit their needs. The research questions are focused on understanding the impacts of the tool on students' behavior, performance, and learning of computing theory; whether students from different types of institutions are impacted in significantly different ways; and the effects of various types of feedback on students' learning. The tool's added functionality, improved usability, and availability as opensource software will encourage its adoption at other institutions and increase its educational benefits. The project, including the upgraded feedback tool and the associated research study, will provide new insights into pedagogical approaches for improving student learning and will help students to be better prepared to develop high-quality software. The NSF IUSE: EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through the Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-07

With the support from the Chemical Synthesis (SYN) program in the Division of Chemistry Professor Ellen Matson of the University of Rochester is studying the hydrogen atom uptake and transfer at the surface of polyoxovanadate complexes. The ability to control the activation and transfer of hydrogen is vital for the implementation of H2 use as a fuel and energy carrier, but also the broader effort to electrify chemical manufacturing. The research investigated in this proposal will achieve atomic-level insights into the transfer of H-atom equivalents on a series of model substrates for interfacial (de)hydrogenation chemistries. Results from this work will inform the design of novel materials for efficient and selective hydrogenation reactivity using protons and electrons as a source of hydrogen. The project will support the training of graduate and undergraduate students in the synthesis and characterization of air- and moisture-sensitive inorganic complexes, as well as mechanistic elucidation. The project will also support a regional meeting of inorganic chemists titled the “Western New York Inorganic Symposium” to foster networks and collaborations across local research and undergraduate institutions. The proposed research implements polyoxovandate-alkoxide and polyoxovanadate-carboxylate clusters for the purposes of elucidating structure-function relationships of H-atom uptake on the surface of reducible metal oxide nanomaterials. The project will leverage both self-assembly and post-synthetic modification of polyoxovanadate clusters to access novel structures that mimic surface reactivity of reduced metal oxides. During the project period, elements that modify the regioselectivity of H-atom uptake at the surface of the polyoxovanadate will be investigated (e.g., heterometal substituted assemblies, assemblies featuring bridging and terminal oxide ligands). The improved knowledge of proton-electron transfer reactions at vanadium oxide assemblies will be used in the context of improving product selectivity of stoichiometric O2 (i.e. H2O, H2O2) with broader implications for reducible metal oxide facilitated electrocatalysis. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-07

Abstract Age-related macular degeneration (AMD) is a leading cause of adult blindness with limited treatment options. AMD can present in two forms: geographic atrophy (dry form) and choroidal neovascularization/ CNV (wet form). Strong evidence links sterile inflammation to AMD pathogenesis, and the FDA has already approved two complement pathway inhibitors for treating geographic atrophy (dry form). However, due to the limited therapeutic impact and adverse effects of complement inhibitors and other approved drugs for both dry AMD and wet AMD, there is an urgent need to identify novel therapeutic targets for AMD. Our recently published data and preliminary studies identified secretory phospholipase A2-IIA (PLA2G2A/sPLA2-IIA), a pro-inflammatory enzyme, as a key molecular player in AMD pathogenesis. AMD primarily affects the retinal pigment epithelium (RPE) cells, with drusen underlying RPE cells as an early pathological biomarker of the disease. AMD iRPE cultures and AMD donor eyes showed elevated PLA2G2A levels in drusen. Furthermore, pharmacological modulation of PLA2G2A in AMD iRPE cultures reduced drusen. In addition, in a proof-of-concept experiment, PLA2G2A overexpression led to AMD-associated pathological alterations (drusen, Bruch's membrane thickening, CNV, and visual deficits) in aged C57BL/6J mice. Altogether, these studies provide strong evidence for a "mutation-independent" pathogenic role of PLA2G2A in AMD. To critically evaluate the role of PLA2G2A in AMD, in this proposal, we will utilize human donor eyes (Aim 1), and both in vitro (patient-iPSCs) (Aim 2) and in vivo (transgenic mice) approaches (Aim 3). Ultimately, the proposed research has the potential to i) increase our understanding of AMD pathobiology, ii) provide a relevant mouse model of AMD, and iii) yield a novel and mutation-independent therapeutic target for AMD and potentially related macular dystrophies.

NSF Awards · FY 2025 · 2025-07

In this project, the PI will investigate the problem of recovering the missing values of a signal using effective and mathematically justified algorithms. The PI will investigate both the discrete case, which has potential applications to the imputation of missing values in data science, and the continuous case, with potential applications in fire detection and image reconstruction. The discrete mechanisms studied in the project lend themselves to numerical investigations where undergraduate students play an important role, contributing to the wide dissemination of the underlying ideas and training of the next generation of mathematicians. In this project, the PI will study a broad-based approach to Fourier restriction that seeks to unify results in discrete, Euclidean, and Riemannian manifold settings. We begin by proposing a restriction theory-based approach to Fourier uncertainty signal recovery in a discrete setting. The PI will employ variants of Bourgain's Lambda(q) theorem to cover the cases that are currently out of reach. This will lead the PI naturally to the study of annihilating pair inequalities where the ideas in the project lead to results in discrete, continuous, and manifold settings. The PI will engage in a systematic study of the uncertainty principle on Riemannian manifolds where we circle back to the probabilistic bounds that arise in the discrete signal recovery part of the proposal. The uncertainty principle on manifolds leads the PI to study random sampling on manifolds where the strong unique continuation property of the Laplace-Beltrami operator plays the key role. The question of the stability of the proposed sampling result leads the PI to study the smallest singular values of the resulting matrices, which have natural applications to the signal recovery part of the proposal. Finally, the PI will develop a comprehensive approach to the spectral synthesis problem previously studied by Agmon, Agranovsky, Hormander, Narayanan, and others. This approach is based on restriction theory ideas and leads to a natural signal recovery question where properties of the classical Helmholtz equation play the key role. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-06

How can a computer be trained to discover musical motifs? How does the brain encode musical features when people listen to music and associate it with their memories? Can we leverage recent advances in artificial intelligence (AI) to make communication easier between deaf children and their hearing parents? These are some of the questions that students will investigate in this Research Experience for Undergraduates (REU) site at the University of Rochester. Students will explore an exciting, interdisciplinary research area that combines computer science, electrical engineering, cognitive science, and music. Each student will be mentored by two or more faculty members from the University's schools of engineering, arts and sciences, medicine, and music. Other activities of the REU site include workshops on career development; scholarship community colloquiums; graduate school preparation; programming for machine learning; and music-focused activities. The goals of this REU are to broaden the horizons of students engaged in computer science research. The site welcomes students from institutions where opportunities for interdisciplinary research combining computational methods, arts and humanities may be limited. Students who are already majoring in computer science will discover that the research in the field is not limited to traditional applications, but can address questions of art, culture, and human psychology. Students with experience in combining computer science with humanistic research are already in great demand in industry and academia and will help define what it means to be a computer scientist in the 21st century. Students in the University's REU will engage in interdisciplinary research that combines machine learning, computer audition, music theory, and cognitive science. These disciplines are united by their use of a common set of formal representations and computational methods; in particular, probabilistic models and machine learning. Research projects include finding neural encoding mechanisms of music listening and memory, designing algorithms for the search and generation of music motifs, developing analysis methods on EEG signals to decode musical minds, inferring public perception about e-cigarettes using large language models, and developing technologies to improve communication for deaf and hard of hearing children. The major objective of the REU is to encourage students to enter STEM graduate programs, but many of the projects will also lead to novel and publishable research in machine learning, music cognition, human computer interaction, and computer vision. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-06

The University of Rochester Cancer Center (URCC) National Cancer Institute Community Oncology Research Program (NCORP) Research Base (RB) has over 35 years of experience conducting cancer control research (CCR) and cancer care delivery research (CCDR). The URCC NCORP RB vision is "to help good people through lousy times when they experience cancer” by reducing cancer- and treatment-related morbidity stemming from toxicities and side effects. Since 2014, 35% (N=2831) of all accrual credits across the entire NCORP network resulted from enrollment of patients and survivors by our Community Affiliates on our 13 active URCC clinical trials. URCC and its Community Affiliates also enrolled 421 caregivers and more than 300 oncologists to our 13 active trials, as well as 1752 patients and survivors to our 29 local pilot studies. URCC successfully enrolled and randomized over 30 individual community oncology practices to cluster randomized trials. Our investigators and staff submitted 8 new concepts/grants, with 18 new concepts/grants currently in development, and 29 active pilot studies. The significant and innovative contribution of URCC research to scientific knowledge and clinical care is evidenced by 1) 197 published manuscripts, 2) 209 presented abstracts, 3) 25 podium presentations at ASCO, 4) 82 outstanding research awards to our investigators, and 5) 2215 investigators, clinicians and staff successfully trained to implement URCC NCORP RB protocols at community sites across the United States. Notable recognition of the significance of research conducted by the URCC RB and its investigators includes: 1) Best of JCO publications for 2017, 2) most cited article in JAMA Oncology for 2017, 3) one of the most significant advances in cancer research and care for 2018, 4) citation of our published research in virtually all existing oncology supportive care treatment guidelines, and 5) leadership by 5 of our RB Executive Committee members in the development of 4 oncology supportive care treatment guidelines. We accomplish our goal of reducing cancer- and treatment-related morbidity by working with cancer patients, survivors, and their caregivers from 592 community oncology practices across the United States to design and conduct CCR and CCDR, including translational outcomes, focused on symptom science. Our research develops and tests novel treatments for toxicities and side effects stemming from cancer and its treatments. We design and conduct phase I-III randomized clinical trials and longitudinal, prospective cohort studies. To meet its responsibilities as a RB and maintain its high level of productivity over the next funding period, the URCC RB will focus its resources and expertise on the following specific aims: Aim 1) to conduct CCR, Aim 2) to conduct CCDR, Aim 3) to conduct translational CCR, and Aim 4) to provide state-of-the-art training in clinical research methods for NCORP investigators and staff. With its proven record of productivity and innovation, the URCC NCORP RB is expertly positioned to continue its pioneering symptom science research in the NCORP Network.

NSF Awards · FY 2025 · 2025-06

This award supports the renewal and continuation of the Research Experiences for Undergraduates (REU) site in Physics at the University of Rochester. The site supports ten undergraduate students per year for ten weeks of summer research in the general areas of physics, astrophysics, and optics with direct research in the sub-fields of nuclear and particle physics, quantum optics and quantum information, condensed matter and nanoscience, astrophysics and cosmology, and plasma physics. Individual guidance and mentoring fostered within the faculty's research groups provides each participating student with the skills to navigate the world of science such as giving scientific talks or writing articles that will lead to the participants’ intellectual development as an independent researcher. The objective of the REU is to offer undergraduate students throughout the nation the opportunity to take part in physics research over a range of topics. Each student works with a faculty adviser on a specific project within the context of the overall research focus of the group. REU students attend weekly presentations by University faculty, tours of University research facilities, and social outings and may also take part in the Department's summer outreach activities. The REU students regularly interact with all REU programs on campus through activities coordinated by the University's David T. Kearns Center. The program concludes with two student symposia (at the Department and University levels), at which each student presents their research; students submit written abstracts and reports of their research experiences. Students are encouraged to continue their projects toward publication and are eligible for additional support to present their results at national student and professional conferences. This site is supported by the Department of Defense in partnership with the NSF REU program. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-06

Providing clean water to people is essential and a great challenge. To help address this challenge, solar energy can be harnessed to purify wastewater or seawater by evaporation and condensation. A potentially efficient method for the evaporation step is to use solar-thermal interfacial evaporation, where solar heating and water evaporation occur together at the interface between air and water. However, interfacial evaporators are usually made of bulk porous materials that introduce many limitations. Recently, the team for this project developed a two-dimensional interfacial evaporator consisting of a metal surface containing microcapillaries. Enhanced wicking in the microcapillaries and efficient light absorbance in the metal produced highly efficient evaporation. This EAGER project will explore the mechanisms underlying the evaporator’s performance with the goal of producing optimal surfaces for high-efficiency interfacial water evaporation. The project will provide opportunities for undergraduates to participate in the research and will also sponsor open-house events for students to learn about technologies used in water research. Previous studies have shown that evaporation is strongly influenced by water clustering at the air-water and solid-water interfaces. To study the superwicking surface effects on water evaporation, two techniques will be applied - calorimetry and transient circular dichroism spectroscopy. The experiments will test the hypothesis that the highly efficient evaporation achieved in the two-dimensional evaporator is attributed to a reduction in the enthalpy of vaporization in the device’s microcapillaries. The outcomes will pave the way to design optimal surfaces for high-efficiency interfacial water evaporation and desalination, as well as to help understand other interfacial processes like corrosion, biofouling, bacterial growth, icing, boiling, and adsorption. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-06

Understanding how the outer shell of the Earth moves and deforms is essential for explaining natural phenomena like earthquakes and volcanic activity. This project seeks to improve knowledge of tectonics by studying the deep structure beneath Africa, a continent that holds key clues about how the interior of the planet influences surface movements. Unusually hot mantle rocks are observed underneath Africa, as well as the East African Rift System, the most prominent and active continental rift on the Earth. Taking advantage of these features, the project will develop a detailed model of the deep structure beneath this continent. It will also revise how its tectonic plates move, and explore interactions between the Earth’s outer shell with the deeper convecting mantle beneath Africa. The results of this research will help increase understanding of fundamental processes shaping our planet. For example, the findings may enhance earthquake hazard assessments, improve models of global plate motions, and provide relevant information to other aligned fields, such as geothermal exploration. This project uses advanced seismic and geodetic data to provide a more complete picture of Earth's dynamic interior. This project will try to advance the understanding of plate tectonics by investigating how the African continent interacts with the underlying convecting mantle. Specifically, it will test a long-standing hypothesis that lithosphere-asthenosphere coupling modulates the influence of mantle convection on Africa’s surface motions, with broader implications for global tectonic processes. The research will integrate seismic and geodetic data from AfricaArray, Global Navigation Satellite System (GNSS) stations, and other sources to develop open-access, high-resolution continental-scale models of the kinematics of Africa, crustal and lithospheric structure, upper mantle seismic properties—including azimuthal anisotropy—and key mantle discontinuities. To test this hypothesis, the project will enhance and leverage the capabilities of the open-source software ASPECT (Advanced Solver for Planetary Evolution, Convection, and Tectonics) to enable improved modeling of lithosphere-asthenosphere viscous coupling at a continental scale. A key objective is to determine whether lithospheric motion in Africa and its surroundings is only weakly coupled to the underlying convecting mantle due to an anomalously hot and low-viscosity upper asthenosphere. Beyond scientific contributions, the project has the following major broader impacts. It will support annual AfricaArray meetings in South Africa and enhance capacity-building efforts through workshops on data science, seismic and GNSS data processing, and access to streaming datasets. These workshops will follow well-established Carpentries lesson structures, with a focus on training new instructors.. An independent professional evaluation will make sure its impacts are maximized. Undergraduate researchers will contribute to the development of seismic tomography models increasing their technical skills. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-06

Project Summary Essentially all multicellular animals exhibit some form of metabolic plasticity in response to environmental or internal cues. This project seeks to increase our understanding of how metabolic and stress response pathways interact and are regulated and at both the cellular and organismal levels, as well as the mechanistic basis for the limits to this plasticity. The focus of this work is on an innovative system, ants, which feature extreme disparity in metabolism between phenotypic classes of individuals (“castes”) within the same nest. Importantly, these differences are not genetic, but instead the product of environmentally-determined plasticity. The species focused on in this work (Harpegnathos saltator) is particularly well-suited for understanding plasticity of stress resistance and metabolism: any individual can be induced to change caste – from non-reproductive to reproductive – in the lab on the order of days, a change that is fully reversible on the same time scale. I show evidence that changing caste results in a rapid, striking shift in global metabolism, consistent across multiple tissues, under the control of behavioral/social stimuli. Importantly, these shifts, which can be recapitulated in vitro, show strong evidence of engaging both metabolic and stress-response pathways typically seen as mutually exclusive, likely due to eusocial evolution uniquely prioritizing very high anabolism as well as long-lifespan in reproductive individuals. Further, comparative analyses reveal strikingly-similar signatures of gene expression between castes of one of the only eusocial mammals, suggesting evolution of eusociality may converge on regulation of these hugely-important pathways in multiple independent taxa. The proposed work will utilize in vivo and in vitro experiments in ants, D. melanogaster, and the Naked Mole-rat to understand how the Unfolded Protein Response (UPR) and MYC-hyperactivity paradoxically appear to both be acting in a novel way to accomplish the metabolic differences between castes, how these differences are regulated organism-wide, and if the same regulation has evolved in a eusocial mammal. We will utilize custom antibodies and perturbations in vitro and in vivo to identify core components and unique upstream effectors, neuronal cultures that transcriptionally recapitulate castes to understand the hormonal regulation of this plasticity, and work with the Naked Mole Rat to understand how these signatures appear to have also evolved in a eusocial mammal. This work will not only shed light on the regulation and evolution of metabolic plasticity at both the cellular and organismal levels, but also how ants uniquely engage multiple conserved, medically-relevant metabolic regulators to uniquely accomplish a high-metabolism stress-protected state not seen in other systems.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY Schizophrenia is a serious psychiatric disorder characterized by hallucinations, delusions, and disordered thinking and behavior that impairs daily functioning. As per the NIH’s Research Domain Criteria framework, we might gain a deeper understanding of this disorder by focusing on basic dimensions of functioning and how they relate to behavior and neural systems. With this in mind, research in recent years has sought to link psychosis with dysfunction in “predictive perception”. According to this framework, perception is an intrinsically predictive process that involves inferring the causes of our sensory inputs by combining those inputs with prior beliefs about the states of the world. And it has been proposed that psychosis is the result of maladaptive inferences based on inappropriately weighting prior beliefs relative to sensory input. However, testing this idea is complicated by the challenge involved in interpreting neurophysiological measures of perception in terms of feedforward sensory activity vs top-down predictions, and by the heterogeneity seen across individuals with schizophrenia. With these issues in mind, we propose to use innovative stimuli to derive EEG responses from the earliest stages of human visual cortex that are not overly complex in terms of their hierarchical generative architecture, and to relate those responses to measures of psychosis across healthy individuals, patients with schizophrenia, and patients with bipolar disorder. Specifically, we will collect high-density EEG from two innovative experiments. The first experiment aims to derive so-called “perceptual echoes” from human visual cortex. These “echoes” are novel measures of recurrent activity in early visual cortex that have been modeled as outputs from a predictive coding architecture. The second aims to leverage a powerful visual illusion to dissociate weak bottom-up stimulus changes from strong top-down predictions. Using the data from these experiments, we will compute impulse response functions that characterize early visual processing. To isolate an index of top-down feedback for each experiment, we will use comparative analyses (comparing impulse response function characteristics across latencies for Aim 1 and across experimental conditions for Aim 2). We will supplement our understanding of these indices – and produce additional dependent measures – by modeling the causal connectivity architecture underlying our impulse response functions. Finally, we will use linear mixed effects modeling to test the hypothesis that top-down predictive processing (as indexed by both impulse response functions and connectivity) relates to positive symptoms of psychosis transdiagnostically. Overall, the project aims to produce robust and interpretable indices of top-down predictive perception that will deepen our understanding of the symptomatology and underlying pathophysiology of psychotic disorders, which in turn, could improve early detection or provide biologically inspired alternatives to the current DSM nosology.