University Of Rochester

NSF Awards · FY 2024 · 2024-08

This award will support The NY 2024 RNA Meeting in the Finger Lakes to be held on October 13th-15th, 2024. The meeting will include participants from a wide range of career stages and research areas, including undergraduates, graduate students, postdoctoral fellows, principal investigators, and scientists in the biotechnology industry. It will be organized through the joint efforts of the Center for RNA Biology at The University of Rochester and the RNA Institute at The State University of New York at Albany. The meeting provides an opportunity to bring together leaders in the field of RNA biology with new investigators and trainees at multiple career levels to present, discuss, and disseminate their work. The conference affords a rich opportunity for broader impacts on the community through (i) participation of diverse researchers, including from groups underrepresented in STEM fields, (ii) advancement of STEM education, and (iii) development of a diverse and competitive STEM workforce by catalyzing partnerships between researchers in the academia and industry. The format of this meeting is designed to maximize attendee exposure to the frontiers of RNA biology through seminars from invited speakers on a range of topics, ‘lightning’ talks by trainees, an extensive poster session, and many opportunities for informal conversations. The meeting topics include nascent RNA metabolism, structural RNA biology, RNA in neuroscience, CRISPR biology, RNA therapeutics, and RNA vaccine development. Meeting participants will thus be immersed in a broad swath of contemporary interests driving RNA biology both in academia and the biotechnology industry. 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 · 2024-08

The goal of the current proposal is to determine the role of monocyte Delta like-4 (Dll4) in cerebral small vessel disease (CSVD) and its impact on cognition in people with HIV (PWH). Dll4 is a Notch ligand usually restricted in endothelial cells (ECs). However, monocytes can express DII4 under pro-inflammatory conditions. This is relevant to the current era of combination antiretroviral therapy (cART), where persistent systemic inflammation is a driving force for the progression of comorbidities. Our preliminary data strongly suggest that DII4-Notch signaling is implicated in altering cerebrovascular function. In vitro, we demonstrate that pro-inflammatory stimuli such as lipopolysaccharides (LPS) or tumor necrosis factor alpha (TNFα) (often increased in HIV infection) induce a robust increase of Dll4 expression in human monocytes and Dll4 secretion (extracellular Dll4, exDll4) from monocytes. Monocytes with high Dll4 expression trigger Notch1 activation to promote a pro-inflammatory status. In vivo, mice injected with exDll4 show impaired blood-brain barrier (BBB) and cerebrovascular remodeling. Of interest, exDll4 inhibits Notch1 activation in human brain microvascular endothelial cells (HBMECs) and Notch2/ 3 activation in human brain vascular smooth muscle cells (HBVSMCs). In clinical specimens, we have found sex differences in exDII4 plasma levels of PWH on cART, elevated in males but not in females compared to HIV uninfected study participants. However, membrane-bound DII4 levels were similar in males and females, suggesting novel pathways that may contribute to the previously reported sex differences in cerebrovascular disease. Based on the observations above, we hypothesize that monocyte DII4-Notch signaling contributes to a monocyte pro-inflammatory phenotype in both male and female PWH. Pro- inflammatory monocytes are more likely to interact with endothelial cells (ECs) and cross the BBB differentiating in perivascular macrophages, thus contributing to neuroinflammation and CSVD. In addition, male PWH have increased levels of exDII4 in circulation, which could further affect the BBB through inhibition of Notch1 signaling in ECs and Notch3 signaling in pericytes. exDII4 also increases vascular remodeling in small arteries and arterioles, leading to ischemia as reflected by lacunae and white matter hyperintensities, typical manifestations of CSVD. We will test these hypotheses by addressing the three aims listed below: Aim 1. To determine, in a longitudinal study, the role of monocytes derived DII4 in brain microcirculation and microstructure integrity. Aim 2. To determine, in an integrated approach, the effects of HIV status, imaging metrics, exDII4, and mDII4 levels on cognitive performance. Aim 3. To define the role of mDll4 on molecular mechanisms of monocyte transmigration and the mechanistic role of exDll4 on vascular cell function.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Natural processes, such as protein expression, cell differentiation, and gene transcription, depend on biomolecules to adopt specific assembly states and secondary structures, primarily shepherded by noncovalent interactions. These noncovalent interactions also scaffold the formation of multicomponent and three-dimensional supramolecular complexes that provide access to architectures with (1) length scales much larger than their individual components and (2) dynamic, reconfigurable structures enabled by the finite lifetime of the noncovalent bond. However, traditional therapeutic and diagnostic interventions favor the use of small molecules with fixed structures to attempt to interrupt or direct these natural processes. We hypothesize that, to fully understand, interrogate, and modulate natural processes, synthetic constructs with specific noncovalent interactions that operate at length scales and with dynamics commensurate with their natural targets are needed. The overarching goal of the proposed research is to exploit the synthetic potential of supramolecular chemistry to develop new noncovalent motifs and reactions to interface with and intervene in biological processes. In pursuit of this goal, one research direction is developing supramolecular mimics of natural chaperones. Protein folding is a chaotic process that relies on natural chaperones to marshal proteins towards their functional structures. We recently discovered a series of amphiphilic molecules that assemble into supramolecular capsules and inhibit the fibrillation of an amyloid beta protein fragment. Future work in this area seeks to capitalize on this discovery to establish structure-function relationships that relate molecular structure, assembly properties, and chaperone-like function, and establish dynamic photoswitches to modulate the hydrophobicity of our supramolecular chaperones in situ and induce protein refolding. Our second research direction will establish new recognition motifs for canonical (Watson-Crick-Franklin, WCF) and non-canonical base pairs in nucleic acids. Though most base-base interactions in DNA and RNA consist of WCF interactions, non-WCF interactions and mismatched base pairs are important structural features, implicated in DNA cytotoxicity and RNA function. Typical approaches to target such structures rely on small molecule intercalators that require identifiable binding pockets. To circumvent this limitation, we are developing bifacial nucleobases that harness inherent base-pairing to target specific nucleic acid sequences and structural folds. In sum, the proposed research program will advance fundamental understanding about the molecular recognition of biomolecular primary and secondary structures and establish new recognition motifs that will underpin the development of future diagnostics and therapeutics.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract Bone fractures in the elderly are a serious health issue due to high morbidity and mortality. New therapies are needed to reduce treatment time and decrease the mortality rate. Cellular senescence is closely associated with aging and aging related diseases, including osteoporosis. However, senescent cells (SCs) are heterogenous, and their roles in fracture repair during aging have not been well studied. We recently reported that SCs in callus impaired age-associated fracture repair through TGFβ1 and clearance of total SCs with senolytic drugs (Dasatinib+Quercetin, D+Q) enhanced fracture repair in aged mice only, indicating the difference of SCs in callus between young and aged mice. With cutting-edge technology, single cell RNA sequencing in mesenchymal cells (CD45-CD31-Ter119-) from callus identified 3 clusters of SCs: TGFβ1+CXCR2+, TGFβ1-CXCR2+, TGFβ1+CXCR2. Very interestingly, TGFβ1+/-CXCR2+ clusters strongly inhibited CaMPC growth, indicating they are detrimental SCs (dSCs). CXCR2 signaling promotes cellular senescence. We found that CXCR2 inhibitor specifically removed dSCs and enhanced fracture healing in aged mice, suggesting removal of dSCs, but keep potential beneficial SCs subsets benefit fracture healing in aged mice. To investigate the potential molecular mechanism, we examined the role of TGFβ1 and tissue inhibitor of metalloproteinase 2 (TIMP2), one of the top expressed SASP in dSCs. TGFβ1 neutralizing Ab enhanced fracture healing in aged mice. TGFβ1 and TIMP2 neutralizing Abs synergistically inhibit the effect of SCs on CaMPC growth. The ubiquitin-proteasome system (UPS) plays critical roles in age-associated bone disorders. Ub-proteomics identified PDGFRβ as one of the most ubiquitinated proteins regulating MPC expansion, and its expression is decreased in bone and callus of aged mice. TGFβ1 induces PDGFRβ ubiquitination and degradation, while TIMP2 decreases PDGFRβ receptor phosphorylation and activation. We further found that CXCR2 ligand, CXCL5, which was increased in callus of aged mice specifically induced dSCs in CaMPCs from aged mice. Thus, we hypothesize dSCs accumulate in callus of aged mice where they produce excessive TGFβ1, TIMP2 and CXCLs, resulting in not only a positive loop of dSC generation from CaMPCs via CXCLs, but also increased ubiquitination and decreased PDGFRβ phosphorylation, and a reduced MPC pool, which can be prevented by selectively depleting dSCs via CXCR2 inhibition. In this application, we will 1) fully characterize dSCs phenotypically and examine if dSCs impair fracture healing in aged mice, 2) investigate whether dSCs affect fracture repair of aged mice by regulating PDGFRβ in CaMPCs via TGFβ1 and TIMP2. Our proposal will elucidate the role of a subset of SCs (dSCs) in aging fracture, identify new mechanisms and novel drug targets, which could lead to interventions for geriatric fractures that are of great morbidity, mortality and healthcare costs.

NIH Research Projects · FY 2024 · 2024-07

A hallmark of Alzheimer’s Disease (AD) is regional brain “iron (Fe) overload”. We hypothesize that life- long exposure to inhaled Fe via air pollution (AP) is a contributor to elevated brain Fe and AD risk. In support of this hypothesis, AP has been linked to increased risk for AD with fine particulate matter (PM2.5) associated with increased risk for dementia, reduced memory, processing speed and increased cognitive impairment, PM2.5 exposures include ultrafine particles and metal contaminants. Of the many redox active metals/trace element pollutants in AP, Fe is often found at the highest concentrations. Studies examining Fe in frontal cortex of AD brains reported an abundant presence of magnetite (Fe2+/Fe3+ iron oxide) nanoparticles, consistent with an exogenous exposure rather than endogenous Fe source. It is critical to note that metal contaminants in AP are not borne equally by everyone. Low socioeconomic status (SES) communities show the highest AP and metal contamination levels (Fe - top percentiles ~0.135 µg/m3). In fact, neighborhood-level SES measures associate with memory and dementia risk. Further support for differential risk and the need to investigate inhaled Fe toxicity comes from the subway systems where Fe levels range 1000 x higher, from 141±81 to 329±116 µg/m3. These “ambient” and “subway” level concentrations provide the rationale for our experiments evaluating the link between inhaled Fe and neurodegenerative risk. Our preliminary data in mice demonstrates that inhaled Fe at “Subway” concentrations (~135 µg/m3) increases brain corpora amylacea, elevates phosphorylated tau protein levels, and results in female-specific hippocampal reductions and memory deficits. (AIM 1). We will evaluate whether AD-associated phenotypes arise at lower, closer to ambient Fe level exposures (1.35 µg/m3) and evaluate a time course of prodromal progression seen in AD studies, while differentiating between exogenous inhaled Fe from endogenous Fe. (AIM 2) Further escalating risk in these communities, poverty-related stress is characterized by a largely uncontrollable set of conditions, comprising a major risk factor for cognitive decline. Higher perceived stress is associated with increased risk for mild cognitive impairment, and two or more stressful life events increases risk for all-cause dementia. We predict that “ambient” Fe and deprived environments with uncontrollable stress exposures will result in AD neuropathology and memory loss, similar to higher “Subway” exposures. (AIM 3) We additionally predict that, conversely, enrichment with controllable stress will improve memory and ameliorate deficits associated with “Subway’ level Fe inhalation. These outcomes will derive from shared biological effects on oxidative stress and ferroptosis, with consequently increased neuroinflammation, reactive astrogliosis with white matter damage and neuronal loss. This research will inform public health policy and prevention to improve quality of life by mitigating cognitive and memory loss. Moreover, these studies advance our mechanistic understanding of how co-occurring environmental stressors, with shared biological consequences, can converge to enhance risk.

NSF Awards · FY 2024 · 2024-07

This is a proposal for support of US participation in a forthcoming international workshop on stochastic partial differential equations, "Stochastic PDEs in Seoul 2024", scheduled to be held in Korea Institute for Advanced Studies (KIAS, S. Korea) on August 12-16, 2024. The organizers are Professors Nam-Gyu Kang (KIAS, S. Korea), Kunwoo Kim (POSTECH, S. Korea), Davar Khoshnevisan (University of Utah, U.S.A.), and Carl Mueller (University of Rochester, U.S.A.). This 5-day workshop intends to bring together leading researchers and highly promising early career mathematicians from across the globe to exchange ideas on some of the cutting-edge questions and topics in Stochastic Partial Differential Equations, a central topic in modern probability theory. The organizers anticipate approximately 20 plenary speakers, and additional participants to take part in discussions on and around the main theme of the workshop. The workshop will be structured so that, in addition to sharing latest developments in their research, participants will have ample opportunities to closely interact, with the ultimate aim of generating new ideas. The principal speakers are expected to come from across the globe, and be leading figures in scientific areas within the scope of the workshop. Nearly half of the speakers are expected to represent the United States, and they are expected to be at various career stages. This proposal is designed to make it possible so that those speakers and some of their graduate-student trainees and postdoctoral scholars can attend and participate. Conference URL: https://sites.google.com/view/spde2024 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 · 2024-07

Liver-related complications continue to pose a significant threat to the health of people living with HIV (PLWH), despite the life-extending benefits of combination antiretroviral therapy (cART). Non-alcoholic fatty liver disease (NAFLD) affects up to 50% of PLWH and can be caused by both HIV infection and cART. The risk factors for NAFLD in PLWH are not fully understood, but hypertension, diabetes, hyperlipidemia, metabolic syndrome, and gut microbiome changes are more common in this population. This study aims to investigate the co-occurrence of NAFLD and HIV infection and their potential impact on brain health. Our hypothesis is that PLWH with NAFLD are at higher risk of persistent blood brain barrier (BBB) dysfunction, metabolite dysfunction, and microcirculation alterations compared to those without NAFLD. These changes may result in more aggressive brain injury and poorer cognitive function, especially in older individuals. To test this hypothesis, we will employ state-of-the-art, non-invasive MRI techniques to evaluate brain injury. Our approach includes developing a novel deep neural network with compress sensing for high-quality reconstruction of highly accelerated clinical chemical exchange saturation transfer (CEST), a molecular MRI technique used to assess metabolic dysfunction. We will compare neuroimaging metrics of metabolite dysfunction, BBB permeability, microcirculation, and neuroinflammation in PLWH with NAFLD versus those without NAFLD. We will also investigate the association between these imaging metrics and blood biomarkers. Additionally, we will assess whether NAFLD in HIV infection leads to reduced cognitive performance, mediated by brain injury as measured by CEST and other imaging metrics. Finally, we will track longitudinal changes in MRI metrics, blood biomarkers, and cognitive performance in PLWH with and without NAFLD and healthy controls. The significance of this research lies in several aspects. Firstly, proposed rapid and high-quality CEST imaging at clinical 3T offers increased sensitivity to disease pathology compared to traditional methods. Secondly, advanced MR techniques can help us better understand metabolic changes, microcirculation, and BBB alterations caused by disease processes. Thirdly, by examining cross-sectional and longitudinal associations between MRI metrics, blood markers, and cognitive scores, we can identify gaps in our knowledge of brain injury and disease progression and their interaction with clinical variables. Fourthly, the use of deep learning models in conjunction with multimodal features may aid in differentiating brain-related abnormalities of NAFLD from HIV, as there is significant overlap in clinical and imaging manifestations. Lastly, the methods proposed in this study may have implications for understanding other brain-related disorders.

NIH Research Projects · FY 2024 · 2024-07

Project Summary The mammalian cochlea is endowed with a robust efferent innervation called the olivocochlear system, that begins in the ventral brainstem as two distinct neuronal clusters containing hundreds of cells. Axons from medial olivocochlear (MOC) and lateral olivocochlear (LOC) neurons travel out cranial nerve VIII where they profusely collateralize in the cochlea to end as thousands of synaptic terminals on outer hair cells (OHC) and primary auditory afferents innervating inner hair cells, respectively. By nature of their connectivity, MOC and LOC neurons are strategically poised to modulate how the cochlea functions at some of the earliest stages of detecting and encoding sound. As reflected in a number of audiometric measures, activation of MOC neurons can give rise to both a suppression and an enhancement of cochlear function by modulating the OHC’s contributions to sound amplification. The release of acetylcholine (ACh) and the activation of nicotinic ACh receptors on OHCs accounts for the MOC-mediated suppression in multiple mammalian species, but the synaptic mechanisms underlying MOC-mediated enhancement have not been identified. This is further complicated by observations that indicate MOC neurons may express a dozen or more different neurotransmitters beyond ACh. As a result, there is a clear gap in our knowledge regarding how one critical signaling arm of the MOC system operates. To facilitate a more complete understanding of MOC function in mammalian auditory physiology, two specific aims will be pursued in the peripheral auditory system of mice. The first specific aim will isolate the MOC-mediated enhancement phenomenon after pharmacological blockade and genetic ablation of MOC-mediated suppression. This will allow for a systematic evaluation of MOC-mediated enhancement over a range of varying auditory and MOC stimulation conditions. The second specific aim will specify and characterize the MOC transmitter and postsynaptic mechanisms required for MOC-mediated enhancement. To complete these specific aims, we will leverage recordings of distortion product otoacoustic emissions (DPOAEs) in the anesthetized mouse before, during, and after electrical stimulation of MOC neurons in the brainstem. Selective pharmacological agents will be administered directly to the perilymphatic compartment to isolate MOC-mediated enhancement as well as identify its underlying signaling components. Immunohistochemical studies will be performed in several strains of mice to localize receptor proteins, integral to the synaptic mechanisms implicated by our pharmacological observations. These studies are significant as they will provide much needed insights into the diverse synaptic mechanisms that the MOC neurons recruit to modulate auditory function in mammals. The data captured by this proposal is critical for probing the functional roles of the MOC system in auditory physiology as well as identifying novel synaptic processes that can be targeted pharmacologically for combating hearing dysfunction.

NIH Research Projects · FY 2025 · 2024-07

The proposed project uses behavioral and neurophysiological experiments in an animal model to explore mechanisms underlying the “modulation filterbank” of human perceptual studies. Envelope fluctuations, called amplitude modulation (AM), are a critical acoustic feature of sound necessary for robust speech perception. Human listeners show diminished AM sensitivity in competing envelope fluctuations of similar frequency, known as modulation masking. Modulation masking is not explainable by classic power-spectrum models, but instead indicates a “modulation filterbank” processing strategy that separates concurrent sounds (e.g., AM targets from noise) that have different AM frequencies. The modulation filterbank is an exciting theoretical advancement because in addition to explaining modulation masking, the model can predict differences in speech-in-noise perception across fluctuating and multi-talker noise sources. Physiological mechanisms of the modulation filterbank are crucial to understand given high relevance to real-world hearing, but remain poorly understood due in part to limited development of animal models. The proposed research will significantly advance our knowledge of the modulation filterbank through operant-conditioning experiments and neural recordings in actively behaving budgerigars. Budgerigars, a parakeet species, are selected based on prior studies showing human-like behavioral sensitivity to many simple and complex sounds. Furthermore, budgerigars and other birds show largely conserved auditory processing mechanisms with mammals from the auditory nerve to the forebrain processing level. Aim 1 establishes the budgerigar as a new animal model of the modulation filterbank using behavioral modulation-masking experiments conducted with operant- conditioning procedures. Preliminary results demonstrate first-ever evidence of the perceptual modulation filterbank in a nonhuman species. Aim 2 quantifies neural mechanisms of modulation-masked behavioral AM sensitivity using extracellular neural recordings from the midbrain and forebrain in behaving animals. Preliminary results support the hypothesis that midbrain average-rate responses explain behavioral band-pass modulation masking, the hallmark of the modulation filterbank, at mid-to-high target AM frequencies. Recordings are made at two processing levels to assess transformation of the modulation filterbank code along the ascending pathway. Aim 3 extends our analysis of the modulation filterbank concept to a real-world listening task in fluctuating noise using “comodulation masking release” (CMR) experiments. CMR is the improvement of tone-in-noise sensitivity observed in fluctuating noise, selected based on recent theoretical studies implicating the modulation filterbank as a key potential mechanism. Aim 3 experiments empirically test a modulation-filterbank mechanism for CMR using behavioral and neurophysiological experiments for the first time in the same species. The proposed project significantly advances our understanding of the modulation filterbank and the role of this exciting model for real-world hearing in noise.

NIH Research Projects · FY 2026 · 2024-07

Human milk (HM) is dynamic - its composition changes during the day, and over time along with infant needs. This chronobiology of HM has long been acknowledged to play a role in infant development and programming but is poorly characterized. While clinical outcomes differ between infants fed at-the-breast (ATB) vs expressed (ie: pumped) HM, how infant input (via suckling) influences HM biology also remains unknown, even though “pumping” is an almost universal practice. As such, our over-arching hypotheses are that HM composition and dynamics, when studied as a biological system, differ between infants fed ATB vs expressed HM, and interrupting delivery of natural HM chronobiological signals to the infant (via feeding expressed HM) impacts infant sleep patterns and microbiome development. Our interdisciplinary team will collect daily HM samples, and extensive metadata from exclusively breastfeeding mothers and infants between 1-4 months postpartum: 60 dyads exclusively feeding ATB (ATB group) and 60 dyads exclusively expressing HM (Express group). Multi-omics analytical platforms will be used to characterize HM hormones, macronutrients, microbiota, oligosaccharides, cytokines, and immunoglobulins to study HM as an ecological system. This novel high-resolution sampling combined with cutting-edge analytical and modeling techniques power these aims: 1) Detect temporal changes in HM composition diurnally and longitudinally and compare these trajectories between ATB vs Express groups. Time-series models and machine-learning analytic approaches will be utilized to infer latent HM dynamics and temporal trajectories, identifying (for the first time) longitudinal and 24-hour temporal patterns in HM composition. We will then determine if and how these trajectories differ between ATB vs Express Groups. 2) Identify relationships between HM composition and dynamics with infant sleep patterns. Compare these relationships and sleep outcomes between ATB vs Express groups. Biometric assessment of infant sleep will be gathered via actigraphy. Bayesian supervised machine learning algorithms will link HM “Lactotypes” and components with sleep outcomes. The resulting algorithm will distinguish if relationships between HM composition and dynamics and infant sleep outcomes differs between ATB vs Express groups. 3) Identify relationships between HM composition and dynamics with the developing infant microbiome, and compare these differences between groups. Machine learning models will identify “Milk Lactotypes” and specifics of HM dynamics that predict the time-course of infant microbiome colonization – a critical marker of future health outcomes. These models will assess how the relationship between HM and infant microbiome differs between feeding ATB vs Express feeding groups. Our study will inform precision nutrition guidance to families feeding expressed HM and will also immediately impact nutrition best-practices for feeding premature infant and milk banking protocols.

NIH Research Projects · FY 2026 · 2024-07

Modified Project Summary/Abstract Section Type 2 diabetes mellitus (T2D) is the major form of human diabetes, accounting for approximately 90–95% of diagnosed diabetes cases in the United States. Our goal in this proposal is to elucidate a novel neural mechanism of glucose regulation that could significantly advance our understanding of the pathogenesis of T2D. The brain renin-angiotensin system (RAS), traditionally viewed as a cardiovascular regulatory system, has recently emerged as a critical part of metabolic and energy-expenditure signaling systems. However, whether the brain RAS play a role in glycemia regulation, and if so, via what signaling mechanisms, constitute major gaps in our knowledge. The (pro)renin receptor (PRR), a key component of the RAS, mediates both formation of angiotensin II (Ang II) – a major bioactive peptide of the RAS – and Ang II-independent signaling in the central nervous system (CNS). In this proposal, we provide important preliminary data supporting the concept that the PRR in tyrosine hydroxylase (TH)-positive neurons in the paraventricular nucleus of the hypothalamus, termed THPVN neurons, is a novel modulator of glycemia. Accordingly, this proposal seeks to uncover a novel role of THPVN neurons and the PRR in the regulation of glycemia and investigate the underlying molecular and synaptic mechanisms. Our central hypothesis is that that PRR signaling in THPVN neurons drives autonomic responses that impair glucose homeostasis, and that activation of this neural pathway contributes to glucose metabolic impairment during HFD consumption. To test this hypothesis, we will use a multidisciplinary approach combining in vivo telemetric glucose monitoring, chemogenic techniques employing DREADDs (designer receptor exclusively activated by designer drugs), in vitro electrophysiology, and TH neuron-specific targeting in the paraventricular nucleus of the hypothalamus. Successful completion of the proposed project will advance our understanding of a novel role and mechanisms of the brain PRR and THPVN neurons in the autonomic regulation of glucose homeostasis and provide a potential therapeutic target for T2D.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract Stem cell transplantation therapies are emerging as some of the most promising methods for treating an array of neurological and neurodegenerative disorders where the primary cause of pathology is cell death. Among the most exciting of these approaches is the transplantation of human Neural Precursor Cells (hNPCs) that are derived from human induced Pluripotent Stem Cells (hiPSCs) to replace neuronal loss. For targeted stem cell therapies to be successful, programmed hNPCs must undergo a complex and dynamic set of processes in vivo after transplantation, including proliferation, migration, and integration into the existing circuit. Although it is accepted that all of these processes are critical to the success of hNPC transplantation therapies very little is known about their dynamics, either in patients or in animal models. The ability to track the changes that hNPCs undergo once in the neocortex, in vivo over the lifetime of the animal, will provide key insights into the mechanisms governing transplant integration, as well as the functional impact that transplants have on existing circuits. The goal of this proposal is thus to develop cutting edge methods for in vivo imaging and neurophysiology to study the structural dynamics and functional impact of hNPC transplantation in adult cortical circuits in the mouse. We are ideally suited to accomplish this goal as we have shown that hNPCs derived from hiPSCs transplanted into the juvenile mouse integrate into mouse cortical and hippocampal circuits. Furthermore, we have pioneered multiphoton in vivo imaging and neurophysiology methods in the mouse that will support the innovations proposed for tracking the structural and functional dynamics of transplanted hNPCs. Using this expertise, we will accomplish the goal of this project via the following 3 aims. In aim 1, we will determine the structural maturation of human NPCs transplanted into the adult mouse using lifetime in vivo 2-photon imaging. In aim 2, we will determine the molecular and cellular identity and characterize the intrinsic biophysical properties of NPCs engrafted into the adult mouse. In aim 3, we will characterize the functional properties of neurons differentiated from transplanted hNPCs in the visual cortex of awake behaving mice.

NIH Research Projects · FY 2024 · 2024-07

The CRE2STEM program intends to contextualize STEM education to the culture, experiences, barriers, and realities of students in their communities. Teachers will be empowered with experiential learning with URMC investigators from biomedical and population health sciences to provide real-world content, resources and consultation to inform the STEM curriculum development. Community partners will facilitate visits and interactions with agencies and organizations engaged in addressing health disparities, low academic performance in high schools and workforce development to inform a culturally responsive classroom education in STEM. Ultimately, our hypothesis is that these two elements will impact : 1) the educational system, and teachers culturally responsive teaching practices, and 2) increase the pool of diverse students with competencies in STEM motivated and interested in careers in STEM and healthcare. To ensure this contextualization, all elements of CRE2STEM will be facilitated within an equal, trusted, dedicated, cohesive, organic, and vetted collaboration with community partners in education known as the Educational Advisory Committee. The CRE2STEM intervention follows diversity, equity, and inclusion principles as the cornerstone to achieve the equality and inclusivity that NY state students need to succeed. Aim 1: Curriculum Development to Enhance Culturally Responsive Education in STEM. This aim will be achieved through a two-week CRE2STEM Summer Institute for 20 STEM teachers (2 cohorts of 10) from RCSD, year-long professional development, and experiential opportunities in the community and with URMC investigators for two consecutive years. Aim 2: Assess the implementation of the CRE2STEM intervention on STEM teachers and students. By supporting teachers with content, pedagogical tools, and the delivery of culturally responsive STEM curriculum materials aligned with NGSS, the CRE2STEM educational program aims to create a stronger connection between students from diverse backgrounds and their STEM experiences. Aim 3: Disseminate classroom resources and a video-based library of exemplary culturally responsive STEM lessons and shared experiences of teachers in a web-based platform.

NSF Awards · FY 2024 · 2024-07

This EArly-concept Grant for Exploratory Research (EAGER) project focuses on new fundamental understanding and early technology development related to energy- and cost-saving defluorination of per- and polyfluoroalkyl (PFAS) chemicals. PFAS are harmful to human health and challenging to break down into stable, benign substances. Emerging efforts to remediate PFAS from water resources have been hampered by high cost and high energy requirements. The project utilizes sustainable solar-assisted electrocatalysis enabled by non-precious materials and highly-basic aqueous electrolytes to achieve complete defluorination of PFAS. The insights gained from this EAGER project will provide fundamentally new strategies for designing electrocatalytic anodes and novel electrolytes, thereby advancing technologies for energy- and cost-saving aqueous defluorination of PFAS. In addition to the fundamental mechanistic outcomes, the project will provide support to the investigator’s contributions to electrocatalysis engineering, and integration of the research with undergraduate education and outreach to high-school students. The project aims to transform aqueous PFAS remediation by providing a fundamentally new quantitative understanding of PFAS defluorination electrocatalysis, while enhancing anode stability, to enable wide-spread use of cost- and energy-effective technology developed in the investigator’s laboratory. The project builds on the investigator’s experience in using pulsed laser liquid-phase synthesis to prepare surfactant-free OH-terminated [NiFe]-(OH)2 nanocatalysts, to ensure well-defined surface conditions in the catalyst microenvironment. Use of hydrophilic carbon fiber paper as the electrode support provides a high anode surface area, to facilitate PFAS adsorption, without restricting mass transport. The project will identify how high concentrations of alkali metal ions, especially Li+, and high basicity aid PFAS defluorination via mechanistic studies in aqueous LiOH electrolytes with systematically varied Li+ or OH- concentrations, while keeping the counter ion concentration constant. In addition, PFAS with different pKa’s (e.g., PFOS, perfluorooctanoic acid, perfluorooctanephosphonate, perfluoroheptan-1-ol, and GenX) - controlled by their sulfonate, carboxylate, phosphonate, and alkoxide headgroups, respectively – will be evaluated with respect to their adsorption properties at the anode and related defluorination efficiency. To enhance anode stability, new approaches will be developed to immobilize surfactant-free [NiFe]-(OH)2 nanocatalysts on hydrophilic carbon fiber paper by maximizing the catalyst–support contact area via sonication and pulsed laser liquid-phase grafting. Taken together, the knowledge gained from the EAGER project will provide fundamentally new strategies for designing anodes and electrolytes, advancing technologies for energy- and cost-saving aqueous defluorination of PFAS. 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 2024 · 2024-07

The amount of radiation emitted by a large number of elementary sources, like atoms or accelerated electrons, is substantially increased by ``coherence,'' which arises when the sources are closer to each other than the wavelength of the emitted radiation. The most intense light and x-ray sources are characterized by a high degree of coherence and have made tremendous contributions to the progress in science and technology. This project investigates the coherence properties of radiation emitted in a collision of a strong laser field with a high-energy electron bunch, with the ultimate goal of producing coherent gamma rays, where a single photon has an energy higher than that of an electron at rest. Gamma-ray radiation can be used for producing matter-antimatter, for investigating nuclear material and handling nuclear waste, as well as for studying medical isotopes. The project combines the theoretical expertise at the University of Rochester with the numerical and unique experimental capabilities at ELI Beamlines in the Czech Republic, strengthening ties between the US and Europe in the field of high-intensity lasers. The project will also contribute to maturing the science case for a potential future NSF OPAL high power laser user facility at the University of Rochester. This project will employ methods from strong-field Quantum Electrodynamics to investigate the radiation emission spectrum from an ultra-relativistic electron bunch colliding with a strong laser field. First, the emission of one and two photons by two electrons will be considered, where it is expected that analytical and numerical results can be obtained. Then, the more general case of several electrons emitting multiple photons will be treated. Methods to enhance coherence effects beyond x-ray frequencies will be developed by working in the full quantum realm and by manipulating the incoming electron beam at the microscopic level. The ultimate goal is to ascertain the feasibility of realizing a gamma-ray free electron laser (FEL), which is one of the most ambitious unrealized goals of the scientific community. The experimental validation of the theoretical predictions will be performed at the ELI Beamlines laser user facility in the Czech Republic using the unique synchronized petawatt-scale laser and electron beam capabilities available at the facility. This collaborative U.S.-Czech project is supported by the U.S. National Science Foundation (NSF) and the Czech Science Foundation (GACR), where NSF funds the U.S. investigator and GACR funds the partners in the Czech Republic. 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 · 2024-07

Project Summary Sexual dimorphisms associated with immunity and autoimmunity are well described. In some instances, these differences have been attributed in part to estradiol or androgen hormone production and signaling; however, while mechanistic data relating steroids to immune function are emerging, there are still significant gaps in our knowledge. Our lab became interested in estrogen effects on the immune system as a result of our work on an unusual disease called lymphangioleiomyomatosis (LAM). LAM is a rare cystic lung disease found almost exclusively in women. The cystic lung changes are caused by small multifocal smooth muscle cell clusters in the lungs that contain mutations in one of the two tuberous sclerosis (TSC) genes. In patients, LAM is highly estrogen sensitive, as it worsens with puberty, pregnancy, and oral contraception, and stabilizes after menopause. To explain the remarkable female predominance of LAM, as well as its estrogen sensitivity, we proposed that LAM smooth muscle cells in the lungs may originate from the myometrium of the uterus. In fact, when we knocked out TSC2 expression in the uterus, all mice developed aggressive myometrial growth that resembled LAM, with 50% developing lung myometrial nodules from the uterus later in life. Mouse TSC2-null uteri were highly sensitive to estradiol, as growth was eliminated with oophorectomy or aromatase inhibitor treatment. In contrast, isolated LAM cells from these mouse uteri, as well as other TSC2-null cells, had little estradiol sensitivity in vitro, suggesting that, in vivo, estradiol promotes LAM progression indirectly. Accordingly, we find that estradiol via ERα stimulates innate immunity in mice by promoting neutrophil production in the bone marrow. We have further shown that neutrophils stimulate TSC2-null myometrial cell growth in large part through the release of neutrophil elastase (NE). Finally, we find that estradiol stimulates expression of a melanocytic marker, GPNMB, and define it as a novel LAM serum biomarker that also serves as a potential therapeutic target. Here we propose to examine the mechanisms by which estradiol enhances neutrophil production in the bone marrow, as well as how estradiol and neutrophils act locally within the TSC2- null myometrium to promote LAM progression. We will also examine how estradiol-induced GPNMB modulates TSC2-null tumor cell growth, focusing on its possible actions as a T-cell suppressor. This work will uncover novel mechanisms of estradiol-mediated changes in immunity that will apply to all aspects of biology, from tumor physiology to infectious diseases to autoimmunity.

NIH Research Projects · FY 2025 · 2024-07

The University of Rochester has a long history of training physician-scientists, with numerous alumni contributing to biomedical research and assuming leadership positions at academic medical centers. There is a continued and growing need for physician-scientists, who serve a unique role in translating research discoveries to the clinic and bringing clinical experiences to the laboratory bench. The main objective of the University of Rochester MSTP (UR-MSTP) is to provide a unique and integrated environment for the rigorous and efficient training of future physician-scientists. This is accomplished by immersion in basic science and clinical exposure through all program years combined with a period of focused research leading to the PhD. Degrees are offered in a wide range of areas that take advantage of the University’s highly collaborative and interdisciplinary environment, including basic biomedical sciences with emphasis on specific organ systems, Biomedical Engineering, population-based degrees in Biostatistics, Epidemiology and Health Services Research, and College-based programs such as Chemistry and Optics. As described in this application, our institutional environment is comprised of outstanding faculty, resources and infrastructure, that provide cutting-edge research and clinical training. UR-MSTP objectives are: 1) Provide an efficient and integrated training experience in rigorous research and clinical activities that imbues trainees with skills to identify important biomedical research questions, translate research findings into clinical practice, and develop productive careers combining research, clinical care, education, and leadership. 2) Support and guide trainees through all phases of their training experience across a broad range of disciplines, highlighting multidisciplinary approaches that will impact medically relevant research and human health care. 3) Develop a community of physician-scientist trainees that encompasses principles of respect, as well as research and clinical integrity, for the betterment of human health. 4) Rigorously, comprehensively, and continuously evaluate the MSTP. 5) Recruit 8 new MSTP students each year to maintain a cohort comprising 60 to 65 trainees, striving to complete both degrees in 8 years. The medical school is fully committed to the MSTP, and is supporting new initiatives to enhance program evaluation, training, and recruitment, including an MSTP Summer Scholars Undergraduate Research Program, resources for mentor training, and a new effort to enhance trainee resilience. We have been successful in filling our slots with highly motivated students who are passionate about biomedical research and successful in competing for individual fellowships, publishing their work, and entering competitive, research-focused residency programs. Coupled with the University of Rochester’s commitment to the MSTP, support from NIGMS will ensure that current and future trainees develop the skills and insights to initiate and lead the translation from science to human health as members of the Physician-Scientist Workforce.

NIH Research Projects · FY 2024 · 2024-07

Abstract Parkinson’s disease (PD) is a progressive and chronic neurodegenerative brain disorder that affects approximately 1 million people in the United States. Parkinson’s disease affects all racial and ethnic populations; however, members of ethnic and racial minorities have been historically underrepresented in PD research. This underrepresentation has biased basic understandings of a disease that is already known to be highly heterogeneous in terms of clinical presentation and symptom progression. In particular, non-motor symptoms experienced by people living with PD are markedly different between individuals, and not well understood in minority populations. These disparities are consequential because timely treatment of non-motor symptoms can improve quality of life and delay disability. Therefore, it is imperative that the PD community broaden its inclusivity by better understanding race- and ethnicity-related disparities of non-motor symptoms in PD. Our objective is to investigate how race and ethnicity influence the occurrence (Aim 1), treatment (Aim 2), and burden (Aim 3) of non-motor symptoms among Black/African American and Latino versus White non- Latino people living with PD. We will use data from the Fox Insight study and the TriNetX platform to address our research objectives. The Fox Insight Study is a groundbreaking, decentralized, online study that has successfully enrolled and followed hundreds of people with PD who are Black/African American or of Latino ethnicity or origin, and thousands of White non-Latino people living with PD. The TriNetX platform is a federated network of > 50 healthcare organizations sharing electronic health records data, and includes thousands of patients living with PD who are of Black/African American race and Latino ethnicity. In Aim 1, these data will be used to compare the occurrence of non-motor symptoms between historically underrepresented racial and ethnic (Black/African American, Latino) populations versus more frequently studied (White non-Latino) populations among people living with PD (Aim 1). Next, Aim 2 will compare frequencies of pharmacologic treatment use for non-motor symptoms between historically underrepresented racial and ethnic (Black/African American, Latino) populations versus more frequently studied (White non- Latino) populations among people living with PD. Finally, Aim 3 will compare the most bothersome symptoms between historically underrepresented racial and ethnic (Black/African American, Latino) populations versus more frequently studied (White non-Latino) populations among people living with PD. At the conclusion of this research project, the goal is to have reduced some of the disparities that exist around the current knowledge of PD heterogeneity in underrepresented populations.

NIH Research Projects · FY 2025 · 2024-07

Abstract Transcriptional regulation is an essential process for proper development that a host of cellular machinery orchestrates. Among these cellular factors is the Integrator complex (INT), a 17-subunit complex that associates with paused RNA polymerase II and is responsible for the 3'-end processing of non-coding RNAs and premature termination of promoter-proximally paused RNAPII. Consistent with a fundamental role of Integrator function, mutations within INT subunits cause neuronal dysfunction, including complex neurological syndromes marked by cerebellar ataxia, intellectual defects, and seizures. Similarly, three zinc finger proteins comprising the ‘Z3 Complex’ (ZNF592, ZNF687, and ZMYND8) thought to be associated with INT also have diverse neurological phenotypes when genetically perturbed. Despite a fundamental requirement of Integrator for gene expression and apparent overlap of neurological symptoms in patients with mutations in INT and Z3 subunits, the molecular basis of this profound connection between Z3-INT and brain disorders is unknown. My preliminary biochemical purifications and proteomics described below indicate that the Z3 complex is strongly bound to INT. The formation of a Z3-INT complex indicates that specific DNA binding proteins can potentially influence INT recruitment to promoter-proximal regions in the genome. Consistently, my RNA-sequencing analyses from cells depleted of Z3 subunits reveal broad transcriptional changes that significantly overlap with changes observed upon depletion of INT subunits. Nothing is known about Z3-INT subunit occupancy during neurogenesis nor how perturbation of Z3-INT expression would affect neural development. This is despite the compelling human patient phenotypes caused by their mutation revealing their importance to brain development. Based on these data, I hypothesize that Z3 interacts with INT to modulate its recruitment and occupancy to promoters, and perturbation of this process leads to disrupted neuronal differentiation. To address this, I will first determine expression and occupancy of Z3-INT during neuronal differentiation. Second, I will elucidate the functional role of Z3-INT neuronal fitness. Third, I will uncover biochemical interactions between Z3 and INT. Completion of these aims will converge to uncover the link between INT and associated transcription factors, Z3.

NIH Research Projects · FY 2024 · 2024-07

Project Summary/Abstract Auditory hallucinations (AH) are experienced by approximately 60-80% of individuals with schizophrenia (SZ), and are often associated with significant distress and functional disability. Many individuals who experience these symptoms do not respond adequately to standard treatments with antipsychotic medication, and/or experience adverse side effects from these treatments. Thus, there is an urgent need to better understand AH pathophysiology to inform the development of novel, targeted interventions. Recent mechanistic models of psychosis suggest that AH may result from a pathological overweighting of expectations relative to bottom-up sensory signals during perception, and that lower-level sensory processing impairments in SZ may contribute to this pathology. Therefore, the goal of the proposed project is to investigate these potential AH mechanisms by leveraging recent advances in the use of electroencephalography (EEG) to index hierarchical processing of natural speech. The specific aims are to evaluate whether AH in SZ are associated with: 1) impaired auditory processing of speech stimuli; and 2) alterations in the effects of prior knowledge regarding speech content on the auditory processing of speech. Fifty-six SZ participants will be recruited, specifically 28 with AH (AH+) and 28 without AH (AH-), along with a group of 28 matched healthy control participants (HC). EEG will be recorded as participants listen to speech segments that are either unaltered or acoustically degraded. EEG responses will be modeled to derive indices of auditory encoding of speech. Measures of the effects of prior knowledge will be based on the lexical predictability of narrative speech, and the manipulation of prior knowledge regarding the content of degraded speech. It is hypothesized that AH in SZ will be associated with impaired auditory encoding of speech and a greater influence of prior knowledge on this encoding, and that within AH+, these two alterations will be related. Results will provide data on unanswered questions regarding AH mechanisms, and will be used to support an NIH grant proposal of a larger, well-powered investigation of AH pathophysiology in psychotic disorders and of potential subgroups with regard to underlying pathology. This work has the potential to inform the identification of novel therapeutic targets for AH, along with biomarkers of underlying pathology that can be used to identify subgroups most likely to benefit from particular intervention strategies. Given the significant unmet therapeutic need this line of work aims to address, and its relevance to transdiagnostic mechanisms of psychosis and mechanistic heterogeneity within diagnostic categories, these efforts are consistent with the public health mission of NIMH and its Research Domain Criteria (RDoC) initiative.

NIH Research Projects · FY 2025 · 2024-07

This T32 application will establish a Multidisciplinary Training Program in Pulmonary Research at the University of Rochester. We aim to provide multifaceted and personalized training opportunities that will endow our trainees with the skills required to become successful independent researchers, educators, and policy makers in the lung health sciences. Our T32 training program involves internationally recognized, well-funded, and experienced faculty mentors at the University of Rochester (UR). Our expert faculty are dedicated mentors, and are committed to providing their trainees with indepth knowledge and the critical thinking skills to apply and communicate this knowledge to diverse audiences. This training program will support three post-doctoral fellows and four pre-doctoral graduate students annually. Post-doctoral trainees can be either MD fellows from any clinical fellowship in the School of Medicine and Dentistry (SMD), or PhD post-doctoral fellows who are typically recruited by individual faculty mentors. Pre-doctoral trainees can come from any accredited biomedical PhD program at the UR. All trainees will be appointed to the T32 only after rigorous review by the Internal Advisory Committee, with careful consideration about timing of appointment for MD trainees. The Training Plan involves five Core Components: (i) Coursework, (ii) Mentored Research and Grant Writing, (iii) Grant Writing and Scientific Communication, (iv) Multidisciplinary Training, and (v) Professional Development. Our T32 has strong institutional support from by the Departments of Medicine, Pediatrics, and Environmental Medicine, and is designed to foster collaborations between basic scientists and clinician scientists. It is led by program leaders who are outstanding mentors, and experienced at addressing challenges faced by PhD and MD researchers. This training program will develop the next generation of scientists conducting high-impact research to improve the health of people suffering from lung diseases.

NIH Research Projects · FY 2026 · 2024-07

Perceived social isolation—commonly known as loneliness—is a psychosocial stressor that is associated with increased mortality, opioid use, and precipitants of relapse among individuals with opioid use disorders (OUD). Despite its association with greater clinical severity among individuals with OUD, there are no efficacy trials of perceived social isolation interventions among individuals with OUD. Importantly, there are effective interventions that can decrease perceived social isolation; however, there are no fully-powered efficacy trials that have directly intervened on perceived social isolation among individuals with OUD. Cognitive-Behavioral Therapy for Perceived Social Isolation (CBT-PSI) addresses negative beliefs that perpetuate perceived social isolation, increase negative affect, and reduce one’s ability to engage in social activities. For an individual with OUD, this is critical as addressing cognitive biases, negative affect, and having a sense that one has and engages social support are key aspects of recovery. The proposed R01 tests the efficacy of this brief, telehealth-delivered, evidence-based intervention, CBT-PSI, to decrease perceived social isolation Participants will be recruited nationally and will be randomized to either (a) therapist-delivered CBT-PSI, (b) therapist- delivered Health Education, or (c) self-guided Health Education. Each intervention will occur across 6 sessions delivered/administered on a weekly basis. The specific aims are to: (1) assess group differences in perceived social isolation among individuals with OUD, (2) assess group differences in opioid use among individuals with OUD, and (3) assess the reciprocal relationship between opioid use and perceived social isolation. Additional outcomes of interest include mental health symptoms, and the quality and quantity of social interactions. Outcomes will be assessed post-treatment, 1-month post-treatment, 3-months post-treatment, and 6-months post-treatment. This project has the potential of having a significant public health impact by evaluating an intervention on a novel therapeutic target for OUD, perceived social isolation. Elucidation of the efficacy of CBT-PSI can help advance prevention and augment existing treatment strategies for OUD.

NIH Research Projects · FY 2025 · 2024-07

Project Summary: The global epidemic of HIV continues to pose a major world health threat with more than 1.5 million new infections diagnosed in 2021. Although significant efforts have been underway for more than 30 years to develop a vaccine to prevent HIV infection, to date, only one trial has shown any significant efficacy at infection prevention. A recent study showed that monocyte gene enrichment correlated with the antibody dependent Fc effector functions thought to be the reason for this vaccine’s efficacy. Monocytes are highly versatile cells that regulate immune response through direct and indirect ways through secretion of cytokines. Monocytes are recognized for their ability to contribute to vaccine efficacy across multiple vaccines, including malaria, influenza and BCG. We hypothesize that monocyte subpopulations play a critical role in regulating development HIV vaccine elicited antibody response through innate help and that, once characterized, can be harnessed to improve vaccine efficacy. We will investigate this by two aims. Aim 1 will evaluate changes in monocyte gene expression following infection, auto-immune disease and vaccination using publicly available data and validate in healthy subjects an. Aim 2 will specifically identify monocyte sub-type specific signatures associated with antibody response after HIV vaccination from four recent HVTN trials using CITE-seq and a novel discrete-state mathematical algorithm with in vitro validation. Dr. Keefer and Dr. Thakar are the ideal mentors for this project given their expertise in HIV vaccine research and systems biology. Through this project, I will develop my computational and translational research and build a foundation from which I can transition to independence as a physician scientist.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Though thought to serve many important functions in overall tendon function, including facilitating both healing and adaptation to mechanical load, the true identity and function of the epitenon has remained elusive due to a lack of genetic markers that specifically target epitenon cells. In preliminary studies, we identified a novel population of GLAST-lineage (GLASTu') cells in the epitenon that contribute to both tendon healing following acute injury and tendon adaptation in response to mechanical overload by differentiating into scleraxis (Scx)expressing tenocytes. Identification of a genetic marker for epitenon cells as well as demonstration of their capacity for tenogenic differentiation has opened an exciting new avenue of tendon research with the long-term goal of understanding the role that epitenon cells play in regulating overall tendon homeostasis and to identify ways to leverage epitenon cell behavior to improve tendon health. During the K99 phase of this award, we established voluntary wheel running as a tool for modeling adaptive tendon growth in mice and generated numerous sophisticated genetic mouse models to facilitate the study of how GLASTu" epitenon progenitors and Sex-expressing tenocytes coordinate to affect tissue-level adaptation. To further explore this relationship during R00 phase of this award, the proposed studies build on our prior work to test the central hypothesis that GLAS Tu" epitenon cells are an indispensable source of tenogenic progenitor cells for tendon adaptation and that signaling between epitenon cells and tenocytes is critical for the tenogenic response of GLASTLic progenitors. Combining genetic lineage tracing with integrated spatial/single-cell RNA-sequencing, we will create a comprehensive spatial and temporal atlas that defines the pathways regulating the coordinated mechanoresponse of epitenon cells, tenocytes, and GLASTu" progenitor cells (Aim 1A), To mechanistically test the hypothesis that coordination between epitenon cells and tenocytes is required for the proper tendon adaptive response to load, we will inducibly deplete either epitenon cells or tenocytes prior to tendon load in complementary experiments (Aim 1 B) and assess how disruption of GLASTu, epitenon cell/tenocyte communication affects the overall tendon adaptive response. Collectively, these data will provide the first comprehensive characterization of epitenon cells and their function in tendon biology.

NSF Awards · FY 2024 · 2024-07

With the support of the Chemical Catalysis and Chemical Mechanism, Function, and Properties Programs in the Division of Chemistry, Professor C. Rose Kennedy of the University of Rochester is studying the development of new ligands that work in cooperation with earth-abundant metals to catalyze organic reactions. Typically, ligands are viewed as inert supports for the metal atoms that mediate the bond-forming and bond-breaking reactions used to make the ingredients of consumer goods, important agrochemicals, and medicines. By contrast, Professor Kennedy’s team is designing systems where tandem participation from the ligand enables chemical reactions that do not occur when using the metal alone. This approach is expanding the variety of molecules that can be produced efficiently from readily available starting materials, meeting a critical strategic need for sustainable manufacturing. Through parallel efforts in the classroom, Professor Kennedy is developing new assessment strategies for large-enrollment introductory organic chemistry classes. This approach is using metacognition and team-based learning to improve student retention and workforce preparation in STEM fields. A mini-summer course for high-school Upward Bound students is also being developed to improve access and inclusivity in STEM fields. Designing homogeneous catalysts that use ligand-enabled delivery of complex, multi-atomic reagents to transition metal centers is a powerful approach to expanding the toolbox of synthetic transformations promoted by earth-abundant first-row transition metals. Towards this goal, Professor Kennedy’s research team is developing a family of multifunctional pyridone ligands that, when used in combination with first-row transition elements such as nickel, shuttle complex reagents through the metal’s secondary coordination sphere. This approach is providing a new strategy for engaging poorly reactive but otherwise appealing transmetallating agents and electrophiles. To understand the synergy between the metal and pyridone ligand, the elementary steps relevant to olefin functionalization and cross coupling are being evaluated in detail using a combination of computational and experimental mechanistic tools. Resulting structure-reactivity-selectivity relationships are then being used to invent new catalytic reactions that combine readily available and user-friendly reagents to generate value-added, C(sp3)-rich building blocks for fine chemical synthesis. In the lab, this award is also supporting hands-on chemistry-research training for University of Rochester undergraduate and graduate students as well as Rochester-area high school and community college students. 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.