University Of Rochester

NIH Research Projects · FY 2025 · 1997-03

The Center for Visual Science at the University of Rochester seeks to renew its NEI P30 Core Grant to support 23 participating investigators engaged in vision research. 13 of the participating investigators hold a total of 17 eligible NEI R01 grants and these investigators will have highest priority access to Core resources. An additional 21 affiliated investigators, who are engaged in vision research but are supported by other sources, complete the Rochester vision community and will have access to Core resources at reduced priority. Vision research at Rochester involves four major scientific themes: Advanced optical technology for vision correction and retinal imaging, cell biology of the normal and diseased eye, the neural mechanisms of vision, and vision in behavior. Investigators represented by each of these themes will be served by four Cores: An Administrative Core to ensure the equitable, fiscally responsible, and scientifically productive distribution of Core technical services, a Computing Core that provides applications programming for hardware control, stimulus generation, data analysis, and modeling, an Imaging Core that provides expertise for histology, microscopy, and low- and high-resolution in vivo imaging in mouse, monkey, rabbit and human, and an Instrumentation Core that provides expertise in mechanical and electrical engineering to develop novel instrumentation for vision research.

NIH Research Projects · FY 2025 · 1995-06

Project Summary/Abstract Osteoporosis is a common disease of aging, caused by a combination of increased osteoclastic (OC) bone resorption and decreased osteoblastic (OB) bone formation. Low-level chronic inflammation (LLCI), characterized by increased levels of pro-inflammatory factors induced by activated NF-κB signaling, contributes to the pathogenesis of age-related osteoporosis by stimulating OC and/or inhibiting OB differentiation. However, the molecular mechanisms by which LLCI induces bone loss remain incompletely understood. Our recently published findings indicate that protein levels of TNF receptor associated factor 3 (TRAF3), which negatively regulates NF-κB signaling, are reduced in the bone marrow (BM) of aged mice. This is because increased amounts of TGFβ released from resorbing bone during aging induce ubiquintin- mediated degradation of TRAF3 by mesenchymal stromal cells (MSCs). This reduction in TRAF3 levels in MSCs leads to increased production of the chemokine, SDF1, and subsequent accumulation of a novel subset of B cell cells (CD19+, B220+ and IgM+) expressing RANKL and CXCR4 (an SDF1 receptor) that we have identified in the BM during aging. We have called this subset of RANKL+CXCR4+ B cells as RCBs for short. RCBs directly induce OC formation and produce a soluble factor(s) that inhibits OB differentiation. Importantly, either plerixafor, a FDA-approved CXCR4 inhibitor, or SM164, an inhibitor of IAP proteins, which prevents TGFβ1-induced TRAF3 degradation in MSCs, increased trabecular bone mass, associated with reduced accumulation of RCBs in the BM of aged mice. Our proposed studies will 1) fully characterize RCBs phenotypically, determine if they are present in humans and if CXCR4 in B cells mediates their accumulation in the BM of aging mice; 2) determine if TRAF3 expressed by MSCs regulates the accumulation of RCBs in BM by modulating SDF1 expression; and 3) determine if plerixafor prevents age-related osteoporosis by depleting RCBs from BM and if targeting it to bone increases its efficacy and reduces adverse effects for the prevention of age-related osteoporosis. Completion of the proposed studies will determine the mechanisms whereby this novel set of B cells contributes to bone loss by stimulating bone resorption and inhibiting bone formation during age-related osteoporosis and importantly, will provide proof of principle that plerixafor or a bone- targeted formulation of it may be a novel treatment for age-related osteoporosis.

NIH Research Projects · FY 2026 · 1995-05

ABSTRACT tRNAs are highly evolved in all organisms for specific recognition by cognate tRNA synthetases, accurate decoding, efficient use in translation, flexibility, and stability. The ubiquitous tRNA modifications are highly conserved in eukaryotes, and many have crucial roles in the yeast Saccharomyces cerevisiae and in human health. Lack of any of several modifications in the tRNA body (outside the anticodon loop) results in growth defects in S. cerevisiae, and is linked to neurological disorders in humans. We study the rapid tRNA decay (RTD) pathway in S. cerevisiae, which targets a subset of mature tRNAs lacking any of four body modifications, due to exposure of the 5' end to the 5'-3' exonucleases Rat1 and Xrn1. RTD also occurs in fully modified tRNA variants with destabilizing mutations exposing the 5' end, and is inhibited in met22Δ mutants due to accumulation of the Met22 substrate adenosine 3',5' bis-phosphate (pAp), which inhibits Rat1 and Xrn1. As little is known about the biology of body modifications in other eukaryotes, we study the evolutionarily distant yeast Schizosaccharomyces pombe, which diverged from S. cerevisiae ~600 million years ago and has facile genetics and molecular biology. Using genetic selection and whole genome sequencing of multiple suppressors of growth defects of body modification mutants, we found that each of two S. pombe body modification mutants target decay of a subset of the hypomodified tRNAs by part, but not all, of the RTD pathway, establishing conservation of the use of this pathway. We also found new interactions between body modifications, the RTD pathway, the ribosome, and a major conserved stress response pathway (the human integrated stress response pathway) in both S. pombe and S. cerevisiae. Our current study of S. pombe pus1Δ mutants, lacking pseudouridine (Ψ), and S. pombe tan1Δ mutants, lacking 4-acetylcytidine (ac4C12), has also yielded new insights. Preliminary results with the pus1Δ mutant show decay of one specific tRNA by the RTD pathway that is responsible for its growth defect, and an unexpected connection between decay and a major conserved pathway that is also linked to the human PUS1 disease phenotype. Preliminary results with the tan1Δ mutants show decay of two tRNAs by the RTD pathway that is responsible for its growth defect, and an unexpected connection between decay and a conserved nuclease not known to have this role. To follow up we will: 1A) Analyze the biology of S. pombe pus1Δ mutants. 1B) Analyze the biology of S. pombe tan1Δ mutants. Despite the importance of tRNA decay, remarkably little is known about the turnover rates of individual wild type (WT) tRNAs or about cellular factors that influence these rates. In addition, little is known about turnover of tRNA ends, although the 3' CCA ends of tRNAs are known to undergo constant repair to ensure healthy growth, and are the focus of several regulatory pathways. To follow up we will 2) Determine tRNA end repair rates and tRNA turnover rates of individual tRNAs, using metabolic labeling and mass spectrometry.

NIH Research Projects · FY 2025 · 1992-07

Goal and aims: The overall goal of this program is to prepare trainees for a research career in biostatistics with application to environmental health or related fields by providing them with strong statistical skills, while deeply embedding them in environmental health science (EHS) research in a supportive and interactive environment. This goal is achieved by the following aims. Aim 1 (Formal training): Provide rigorous training in advanced statistics, with additional training in epidemiology and environmental health, through graduate-level course offerings. Aim 2 (T32-specific training) has two sub-aims. Aim 2a: Deeply involve all trainees in collaborative EHS research under co-mentorship of a Biostatistics and an EHS trainer, while providing additional training in reproducible research and improved communication skills; and Aim 2b: Augment EHS training with specialized T32 informal seminars and lab tours in a supportive environment that promotes trainee interactions. Administration and oversight: The program is administered by the Department of Biostatistics and Computational Biology (DBCB), in collaboration with the Departments of Environmental Medicine and Public Health Sciences. There are 14 faculty trainers, six of whom are from DBCB. Program oversight is provided via monthly meetings of the T32 Executive Committee and annual meetings with the External Advisory Board and makes use of trainee evaluations. Training: The DBCB offers a PhD degree in Statistics, with an optional concentration in Bioinformatics and Computational Biology. Training for Aim 1 is provided by the rigorous and state-of-the-art Statistics PhD curriculum, augmented by coursework in epidemiology and environmental health / toxicology. T32-specific training for Aim 2a is achieved by embedding trainees in real-world EHS research, such as the Seychelles Child Development Study that examines neurodevelopmental effects of prenatal mercury exposure from fish consumption. Under co-mentorship of a DBCB and an EHS trainer, trainees receive structured training in reproducible research and communication, implement a data analysis plan, and produce well-documented files that explain the methods and give results. Additional T32-specific training under Aim 2b comes from specialized lab tours and bi-weekly T32 informal seminars that provide additional EHS background and opportunities for practice presentations and trainee interactions. Recruitment: The DBCB holds annual Open House events that have been highly successful in recruiting well-qualified PhD applicants. Predoctoral T32 trainees are recruited from among the current Statistics PhD students, typically after two years in the PhD program. Postdoctoral trainees are recruited via advertisements in relevant job boards and professional societies. Trainees present their work at local and national conferences. Mentorship by T32 trainers and overall experience with the program were very positively rated in recent evaluations by current and past trainees. Slots: The program supports one postdoctoral and three predoctoral trainees.

NIH Research Projects · FY 2025 · 1992-07

We propose to explore the role of the medial olivocochlear (MOC) efferent system in enhancing and “sharpening” the encoding of complex sounds. We will use extracellular recordings in awake animals of inferior colliculus (IC) and ventral nucleus of the trapezoid body, where MOC neurons are located. We also propose psychophysical studies in humans, click-evoked otoacoustic-emission measurements, and a new computational model that includes efferent pathways. In previous grant cycles, we discovered a novel neural- coding strategy based on relatively slow fluctuations in the responses of auditory-nerve (AN) fibers, referred to as neural fluctuations (NFs). For listeners with normal hearing, contrasts in NF profiles along the tonotopic axis provide a robust code for spectral peaks and valleys across a wide range of sound levels and frequencies, as well as in noise, but NF contrasts are adversely affected by sensorineural hearing loss. NF contrasts are shaped by peripheral tuning and nonlinearities, which are in turn strongly affected by cochlear gain, motivating our focus on the MOC system in this application. The MOC has traditionally been described as the hub of a short reflex loop, with wide-dynamic-range inputs from the cochlear nucleus and an output that projects directly to cochlear outer hair cells to modulate cochlear gain. An assumed role of the efferent system is to increase the dynamic range of neurons, reducing rate saturation. It has not been possible to test this assumption using AN recordings, but cochlear nucleus recordings in unanesthetized animals reveal that responses are saturated at moderate levels and dynamic ranges are not increased, bringing into question this presumed function of the efferent system. We propose a new concept: a purpose of the efferent system is to maintain and enhance, or sharpen, NF contrasts. A less-studied but major input to the MOC descends from the IC. Because nearly all IC neurons are sensitive to slow fluctuations on their inputs, NF contrasts are represented by the profile of rates across the population of IC neurons. We hypothesize that IC input to the MOC provides the NF-driven signal that is required by a control system that maintains and enhances NF contrasts. The IC-rate profile, combined with the wide-dynamic-range input from the cochlear nucleus, provides the efferent system with the information required to control NF contrasts across a wide range of acoustic conditions. Exciting preliminary results support the hypothesis that this system actively sharpens the representation of complex sounds. Our new computational model that includes efferent pathways provides testable predictions for IC and MOC physiological responses and for psychophysical performance in human listeners, with varying degrees of sensorineural hearing loss. Understanding nonintuitive effects of different degrees of sensorineural hearing loss on NF profiles, in the context of dynamic MOC feedback, provides new insight into the perceptual consequences of sensorineural hearing loss, and points towards novel strategies to aid these listeners.

NIH Research Projects · FY 2025 · 1990-09

Twenty-eight faculty of the Center for Visual Science (CVS) at the University of Rochester request renewal of support for a pre-doctoral and postdoctoral training program that emphasizes four broadly defined areas of vision research: (1) Advanced optical technology for vision correction and retinal imaging, (2), cell biology of the normal and diseased eye, (3) neural mechanisms of vision and (4) vision in behavior. Training faculty have extensive cross-campus and cross-department collaborations, a strong record of mentoring and high research funding levels. Training is interdisciplinary, drawing particularly on the unique technical and intellectual resources of CVS. It covers a broad range of basic and clinical problems in vision but emphasizes approaches that link visual performance to underlying biological mechanisms. The program has a strong record of trainee productivity, PhD student retention and fast average time to PhD. Similarly, postdoctoral trainees overwhelmingly pursue scientific careers, with significant numbers entering tenure-track positions in academia. Trainees have a good record of subsequent individual training and research funding, as well as successful research and research-related career paths. For our renewal application, we request support for 5 pre-doctoral trainees per year, who will generally enter the program through the Departments of Brain and Cognitive Science, Biomedical Engineering, the Neuroscience Graduate Program and the Institute of Optics. Students will take core courses plus advanced seminars in visual science, augmented by courses from the departments through which they entered the program. Concurrently with course work, students complete research projects in CVS preceptor labs. Finally, we also request support for two postdoctoral fellows per year. Postdoctoral training has a heavy emphasis on research performance, productivity and communication. All trainees take part in topical workshops, special topics seminars, regular colloquia, research talk series, the CVS retreat, and the biannual CVS Symposium.

NIH Research Projects · FY 2025 · 1990-07

Since 1990, The University of Rochester’s Department of Neurology has trained over 80 post-residency physicians and other post-doctoral clinical neuroscientists in its Experimental Neurotherapeutics (ExNT) (NINDS T32) Training Program. The opportunities to translate neuroscience discoveries into clinical trials and clinical care continue to increase rapidly. This translation requires a cadre of specialty-trained clinician neuroscientists responsive to the increasing pace of scientific discoveries, the growing burden of neurological disease, and the emerging approaches and techniques to accelerate therapeutic development. Rochester’s ExNT Training Program, now in its 34th year, is prepared to meet the challenges of a tidal wave of new treatments and opportunities. We will expand our world-class roster of Program Faculty (from 38 to 48) to provide a robust training environment across the increasingly subspecialized fields within neurology. We have changed the mPIs to include a Biostatistician who has been a program mentor since 1990 and have appointed a new Lead Biostatistician and 3 additional biostatisticians to maximize the scientific rigor of training. The proposal builds on the momentum of our prior funding period by training in new areas of cutting edge neurotherapeutics research, strengthening mentorship training, utilizing novel approaches to teaching, and infusing the curriculum with translational research principles stemming from initiatives of this program. The curriculum covers core didactics in experimental neurotherapeutics and an integrated approach that combines face-to-face, online and hybrid learning methods to serve multiple needs and ensure comprehensive education and customized training opportunities for each trainee. Training will occur in a structured environment with a multifaceted mentor team (including Clinical and Biostatistical Mentors) and guided by a Research Career Development Plan. We will increase the perspective of role models by establishing a T32 Alumni and Collaborator Council which will contribute to program seminars and workshops and expose trainees to an increasing number of perspectives, career paths, and opportunities. The program is also strengthened by collaborating with the Experimental Neurotherapeutics program at the NINDS and by piloting a research exchange program with trainees from other institutions. We have also appointed an experienced Program Evaluator and an External Advisory Committee to enhance our approach to evaluating the program, trainees, and mentors. This application seeks support for 4 post-residency trainees per year with 2-4 new trainees accepted into the program annually. The training program infrastructure is also utilized by trainees supported by other funding sources, so that a class of 6-12 fellows are training at any given time. This ExNT Training Program will continue to build on its history and train the next generation of independently funded leaders in experimental neurotherapeutics who will transform the research landscape and accelerate clinical trials that maximize impact, access, and enrollment for all people with neurological disease.

NIH Research Projects · FY 2024 · 1989-09

Project Summary There is growing consensus that dysfunction of cortico-striatal circuits is a key component of psychiatric illnesses, particularly those that involve abnormalities in incentive-based learning, goal-directed behaviors and habit formation. These dysfunctions reflect changes in network structure and dynamics that likely begin during postnatal development. The goal of this application is to gain insight into the anatomic substrates underlying integration across reward/motivation, cognitive, and motor domains in via cortico-basal ganglia circuits and the early postnatal development of these connections. We have previously demonstrated the convergence of motivation and cognitive circuits via the basal ganglia. In this application, we include the motor system in addition to sampling the entire prefrontal area, creating a comprehensive fronto-striatal connectome. Using computational tools, we will use those results to develop a probabilistic map fronto-striatal connections. In addition, our preliminary results demonstrate that early postnatal myelin development varies not only in frontal grey matter areas, but also between layer within areas. We will build on these results to evaluate postnatal development of frontal inputs to the ventral striatum. Aim 1 combines conventional tracing experiments with computational tools to develop a complete map of fronto-striatal connections, identifying areas in which fiber from diverse functional regions of cortex converge in the striatum. Aim 2 will examine postnatal myelin expansion during early postnatal development compared to adult animals. Aim 3 will bring together results from Aims 1 & 2 to determine potential changes in FC-striatal connectivity and its relationship to cortical myelin expansion during early postnatal development.

NIH Research Projects · FY 2025 · 1986-09

Project Summary/Abstract The T32 Predoctoral Training Program in Immunology (PTPI) has been successfully training the next generation of leading researchers, critical thinkers, and communicators in immunology for over 35 years. The astonishing recent successes of immunology at the forefront of several health areas, from immunotherapy of cancer, autoimmunity, aging and inflammatory disorders to SARS-CoV-2 vaccines, as well as the rapid transformation of the technological and methodological landscape, raise challenges and opportunities for the new generation of immunologists. To adapt to this evolution, the objectives of this PTPI competing renewal are to both preserve and build upon its effective foundational principles with additional initiatives and innovations to better prepare our trainees for future challenges in science and society . Guided by a new logic model, the PTPI will continue to provide learners with in-depth immunological knowledge, critical thinking skills to apply this knowledge, the ability to communicate efficiently at all levels and a dynamic independent research experience that will lead to new discoveries by maintaining 7 foundational principles: (1) Wide trans-disciplinary opportunities for training with basic and clinical researchers in a broad range of immune-focused research; (2) Autonomy-supportive educational methods that encourage self-directed learning; (3) Emphasis on collaborative research; (4) Emphasis on scientific rigor and reproducibility at all levels of graduate education, scientific development and professional conduct; (5) Institutional commitment to cutting- edge expertise/technology in immunological concepts and experiments; (6) An innovative Broadening Experiences in Scientific Training Program URBEST (MyHub); (7) Scientific communication to peers and the broader public. This foundational framework will be reinforced by additional innovative initiatives: (a) Consolidate and expand immune-related research fields by diversifying our mentors over the whole institution that include 43 faculty in 22 different basic and clinical Departments and Centers; (b) Enrich our mentor pool by adding more junior faculty mentors who will be coached by our current mentors; (c) Formalize and train scientific rigor and reproducibility during monthly PTPI scientific meetings; (d) Personalized bioinformatic training that can be expanded and specialized toward each trainee’s needs; (e) Strengthen trainees’ critical thinking and understanding of the grant study session process; (f) Develop team-based communication products such as videos for non-scientific audiences; (g) Alternate yearly in-house and regional T32 training days symposia; and (h) Conduct external program evaluation by Dr. Geleana Alston a professional and experienced evaluator. We anticipate that this reinforced program will better prepare our students to enter the immunological workforce and become leaders in contemporary immunology.

NIH Research Projects · FY 2025 · 1978-07

Funds are requested to support the Rochester Toxicology Training Program. There are pressing societal demands to identify and evaluate the impact of an ever-increasing array of environmental chemical, physical, and social stressors on human health. The overall objective of this Program is to provide pre- and postdoctoral training for the next generation of talented, independent toxicologists and environmental health scientists with critical thinking skills who will conduct novel research and actively transform their findings, and findings from others, into new information. This information will then be translated for use by scientists, public health and medical professionals, governmental and other agencies, and the public to improve overall human health and well-being. This Program is distinguished by its exceptional environment for training in toxicology, as evidenced by the success of prior trainees, the remarkable collegiality and extensive collaborations amongst faculty and trainees, a broad base of research support, and its strong leadership and institutional commitment. The Program is dedicated to meeting the needs of all trainees and supporting their individualized goals for careers in academia, government, and industry. The Program’s framework is based on the philosophy that training for the future workforce requires multidisciplinary and interdisciplinary approaches, close working relationships between trainees and their mentoring teams, and a culture that supports critical thinking, autonomy, and career development. The Program takes advantage of extensive expertise and resources that are available at a major academic medical center by reaching beyond a single department. The Program is housed in the Department of Environmental Medicine, yet the 31 faculty mentors come from 13 basic science and clinical departments and divisions within the University of Rochester School of Medicine and Dentistry. Faculty research spans the entire spectrum of toxicology, from molecular mechanisms and cellular processes to whole animals and human populations. There are 7 keystone research areas (Neurotoxicology and Behavioral Toxicology, Pulmonary & Cardiovascular Toxicology, Developmental & Reproductive Toxicology, Immunotoxicology, Musculoskeletal Toxicology, Dermal Toxicology and Endocrine Toxicology) that are rooted in contemporary themes that include particles and air pollution, molecular-genetic modifiers of toxicity, developmental origins of health and disease, epigenetic regulatory systems, and social determinants of disease. The Program is also tightly integrated with other training programs, as well as research and professional development support centers at the University. Program refinements include adoption of changes to the didactic curriculum, addition of new environmental health research expertise, and implementation of holistic review of Program applicants. Continued support of the Rochester Toxicology Training Program will ensure that a reliable stream of exceptionally well-prepared PhD-level toxicologists will be ready to meet the growing demands of the today’s health science workforce.