University Of Rochester

NIH Research Projects · FY 2024 · 2020-09

Project Summary Human vision relies on rapid eye movements called saccades that occur a few times every second. These saccades bring peripherally identified objects to the fovea for high resolution inspection. This split-second sampling of the world defines the perception-action cycle of natural vision and profoundly impacts perception. While much is known about the neural mechanisms involved in the onset of this cycle, how targets are selected before saccades, virtually nothing is known about how pre-saccadic representations would impact processing of post-saccadic information about targets that now appear at the fovea. The proposed research addresses fundamental questions about how pre- and post-saccadic visual information are combined across saccades to maximize information for attended targets. Experiments will be performed in the common marmoset, a New World primate whose smooth cortex affords advantages for recording with high-density silicon arrays across cortical representations and in the longer term for imaging and optogenetic manipulation of large scale neural circuits. In Aim 1, we will test if pre-saccadic information is enhanced in early visual cortex to favor higher acuity information that is most relevant to the fovea and thus could provide a “foveal preview” to prime post- saccadic processing. In Aim 2 we test if pre-saccadic enhancement is target specific and involves a selection of target features, such as orientation or motion. In Aim 3 we record from foveal populations in early visual cortex to determine how pre-saccadic selection alters post- saccadic processing, and specifically, if pre-saccadic feature selection of the target biases processing to favor the continued selection of the target at the fovea based on increasing gain for its features. This research will provide the first evaluation at the level of single neurons and neural codes of post-saccadic foveal enhancement and the role of pre-saccadic target selection. This has broader impacts for understanding attention under natural viewing conditions where the eyes parse visual scenes, and more generally, for how sensory-motor predictions influence visual perception.

NIH Research Projects · FY 2024 · 2020-08

Acute and chronic tendon injuries are among the most common musculoskeletal health problems. Typically, an injured tendon experiences fibrotic scarring that leaves the tissue mechanically compromised and prone to debilitating adhesions that impair joint function. In a fibrotic tendon scar, the cell-cell and paracrine signaling between inflammatory cells, such as macrophages, and tendon fibroblasts activate the latter into fibroproliferative myofibroblasts, ultimately differentiating into a senescent phenotype. Our previous studies using next-generation sequencing and gene set enrichment analysis mechanistically linked fibrosis and senescence in injured mouse tendons with TGF-beta activated mTOR signaling. To further elucidate this pathology, the goal of this proposal is to engineer a microfluidic human tendon-on-chip (hToC) system and use it to more accurately model the biological aspects of the inflammation and fibrosis in injured tendons. In the UG3 phase of this proposal, the chip will be fabricated featuring a multicompartmental design and microfluidic channels to incorporate a fibroblast-seeded collagen hydrogel and simulate vascular blood flow, respectively. Ultrathin, highly permeable, and optically transparent porous silicon membranes (SiM) will separate the hydrogel from circulation and provide a substrate for an endothelial barrier in between. The signaling between the fibroblasts, hydrogel-resident- and circulating-macrophages, and endothelial cells will be enabled through nanoporous SiM (~60 nm), while a microporous SiM (~ 8 µm) will allow extravasation of circulating macrophages and infiltration of the hydrogel under TGF-beta stimulation. To allow for a patient-centric chip, tendon fibroblasts will be used to create the tendon hydrogel and to reprogram donor-matching iPSCs to derive the endothelial cells and macrophages, respectively. An additional innovation will be the integration of label- free photonic sensors into the microfluidic device to allow on-chip sensing, which has been long appreciated as a critical, unmet need for organ-on-chip devices. The UG3 studies will use the chip to validate the role of mTOR in the disease model and identify biologically relevant biomarkers. In the UH3 phase, we will utilize the chip as a pre-clinical trial platform for testing efficacy and safety of FDA-approved mTOR inhibitors as potential disease modifying drugs, and as a drug screening platform to identify and prioritize safer and more potent inhibitors of mTOR and senescence in tendon injury for clinical trials. To successfully complete this innovative project, we have assembled a team of accomplished experts in tendon tissue engineering and surgery, immunology, iPSC technology, GMP cell manufacturing, nano- and micro-fabrication, sensor technology, and high throughput screening. The proposed studies will develop a human microphysiological system to catalyze clinical trials and accelerate drug discovery for acute and chronic tendon injuries.

NIH Research Projects · FY 2024 · 2020-08

Low-income, minority teenagers have disproportionately high rates of asthma morbidity, including excess risk of emergency department visits, hospitalizations, and death from asthma. Despite well established guidelines, under-treatment for asthma is common, particularly for poor urban teens. Our prior work has demonstrated that school-based directly observed therapy (DOT) of preventive asthma medications can improve outcomes for young, urban children with persistent asthma. We have also found that school-based telemedicine can effectively facilitate assessments by primary care providers (PCPs) for preventive medication prescriptions for DOT and for follow-up care. We recently conducted a study for teens with persistent asthma which included a trial of DOT of preventive medications at school paired with motivational interviewing (MI) counseling to promote independent adherence. While this program successfully improved medication adherence, it had a limited effect on asthma symptoms, and in particular many of the teens with moderate to severe persistent asthma at baseline continued to experience poor control despite the intervention. This was at least in part because for many of these teens, the medications initially prescribed for DOT were not optimally adjusted by PCPs and their asthma was undertreated. We realize that this program may be insufficient for these teens (>½ of the overall sample), since access to recommended specialist consultation for medication step-up or management of co-morbidities was not included. Further, while education and self-management support are critical for this age group, the MI counseling in this program required resources for several in-person visits. We now aim to test a novel, developmentally appropriate and scalable model of care to ensure optimal guideline- based treatment for urban teens with difficult to control asthma. The Telemedicine Enhanced Asthma Management-Uniting Providers for Teens (TEAM-UP Teens) program includes 3 core components: 1) An optimized asthma management plan developed at the start of the school year via a real-time, synchronous school-based telemedicine visit that directly connects the teen to an asthma specialist, 2) School-based DOT to implement the medication plan and allow for teens to experience the benefits of consistent therapy, 3) Follow-up telehealth visits with a nurse asthma educator to facilitate ongoing care and provide developmentally appropriate self-management support. In response to PA-18-722; Improving Patient Adherence to Treatment and Prevention Regimens, we propose a full-scale randomized trial of TEAM-UP for Teens vs an enhanced care (EC) control group (n=360, 12-16yrs). We will capitalize on the existing community infrastructure by implementing both telemedicine visits and DOT in schools. We will assess the effectiveness of TEAM-UP for Teens in reducing morbidity and improving guideline-based care (primary outcome: symptom-free days at 3, 6, 9, and 12 months) versus EC. At the study's completion, the program will be better defined as a sustainable means to improve care and reduce morbidity for high risk teens with moderate to severe persistent asthma.

NIH Research Projects · FY 2024 · 2020-08

Vertigo/disequilibrium is a frequent medical complaint for individuals with peripheral vestibular disorders or after concussion, especially individuals with lengthy recovery periods. Concussion and vestibular disease often result in vertigo/disequilibrium, abnormal eye movements, altered self-motion perception, and imbalance. Degraded vestibular perception has recently been linked to balance problems. Despite existing therapies to retrain balance and reflexive eye movements, little is known about the role that self-motion perception plays in the recovery from persistent vertigo/disequilibrium or how to effectively re-train these abnormal perceptions. This career development award will establish Dr. Eric Anson as a clinician scientist with expertise in human vestibular research including basic science ranging from physiology to perception and translational science to enhance the care and quality of life for individuals experiencing chronic dizziness/vertigo. This K23 will ensure Dr. Anson develops expertise in 3 primary domains: 1) Advanced concussion management training; 2) Influence of cognition and emotion on SmP; and 3) statistical methods, perceptual psychophysics, and vestibulo-ocular reflex (VOR) adaptation. Dr. Anson has assembled a multi-disciplinary team of experts in concussion management (Jeffery Bazarian, MD, MPH), cognitive and emotional impacts on balance (Mark Carpenter, PhD; Jeffery Staab, MD), vestibular adaptation (Michael Schubert, PT, PhD), and perceptual psychophysics (Benjamin Crane, MD, PhD; Mark Carpenter, PhD; Jeremy Jamieson, PhD) to facilitate achievement of his goals. Dr. Anson will conduct a series of studies to answer these important questions. He will investigate whether different disease states (concussion and vestibular disease) with similar symptoms lead to differences in self- motion perception (Aim 1). He will determine whether vestibular reflexes and vestibular self-motion perception adapt independently (Aim 2). He will use balance-related anxiety at high heights to investigate the link between emotional regulation, body sway, and self-motion perception (Aim 3). This research plan leverages unique existing resources at the University of Rochester including the CTSI and equipment in the labs of Drs. Anson, Crane, Bazarian, and Jamieson. Dr. Carpenter’s research lab provides access to unique resources for exploring balance-related anxiety as a stressor and training methods to enhance self-motion perception. Dr. Staab’s clinic and research lab provide access to unique resources for training in cognitive behavioral therapy and patients with behavioral variables that contribute to persistent vertigo. The proposed training and mentored research are consistent with the NIDCD strategic plan for research in hearing and balance, specifically addressing current understanding of self-motion perception in health and disease. The proposed training will be the foundation for future R01 applications using self-motion perceptual training to enhance current vestibular rehabilitation, improving quality of life for individuals with vestibular disease or concussion.

NIH Research Projects · FY 2024 · 2020-07

The goal of this Neuroscience Training Program is to generate highly creative and productive neuroscientists who are broadly trained in neuroscience, well trained in their research specialty and equipped to address tomorrow’s important neuroscience questions in a broad range of neuroscience-related careers. The University of Rochester has recently made neuroscience the number one priority in its strategic plan, allowing growth in neuroscience research resources, and an expansion of training opportunities. This application takes advantage of this opportunity to expand and enhance graduate training in neuroscience, creating a catalytic and diverse cohort of trainees. Training support is requested for 6 predoctoral students in each of 5 years. This support will be used exclusively for broad and basic support of students in their first two years of graduate study. A diverse and interactive faculty composed of both basic and translational researchers dedicated to excellence in teaching and collaborative research, and committed to neuroscience training fosters a nurturing training environment. These experienced training faculty, with strong records of extramural funding, offer research training opportunities in a wide variety of neuroscience disciplines. Core elements of our training program include: 1. Core and elective coursework as well as discussion of current literature in required weekly journal clubs and seminars; 2. Training in oral and written communication; 3. Training in ethical conduct of research; 4. Training in experimental design and statistical analysis; 5. A strong focus on mentoring from thesis advisors, committees, as well as other faculty and students; 6. Career development leveraging the program Broadening Experiences in Scientific Training (UR BEST) and the Center for Professional Development to provide students with opportunities to follow their own career path. We propose to further enhance training by developing a new curriculum that allows students to develop quantitative skills through a required summer-long course on data analysis and computation using MATLAB as a platform, and a separate annual workshop that addresses issues in rigor, reproducibility and ethics in an on-going hands-on fashion. We will continue to strengthen our already successful strategies to recruit and nurture minority and women students and to provide all of the trainees with the essential skills to become independent scientists with an appreciation for the ethical conduct of research. These trained scientists will provide the next generation of neuroscientists who will further advances in basic science and translational studies, teach future generations, set science policy and alter the landscape of neuroscience through many different paths.

NIH Research Projects · FY 2025 · 2020-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The University of Rochester has worked to distinguish itself as an internationally recognized center for excellence in research, in part by training the next generation of scientists studying the molecular bases of human diseases. However, with increasingly rapid advancements in scientific techniques, the need for greater attention to rigor and reproducibility in research, and the recognition that today’s students use their PhD degrees in a wide range of careers in the biomedical sciences, there is a need to augment the institutional training of graduate students. This T32-sponsored Training Program significantly enhances our institutional training activities to augment the development of students’ skills in initiating, conducting, interpreting, and presenting rigorous and reproducible biomedical research with increasing self-direction. Moreover, T32 mentors will guide students to become more collaborative, and to understand fields ranging from cellular biology to the molecular behavior of molecules, to computational analyses of large data sets. T32 offerings will equip students with the tools and backgrounds to enable them to think broadly in terms of career choices, and to be inculcated in the skills and knowledge required for success in a professional environment. Our program will imbue students with skills in the ethical conduct of research, and in workplace professionalism. We will accomplish these goals through T32-sponsored courses and activities that ensure a broad knowledge of emerging technologies, cutting-edge methods, and skills required for rigorous experimental design, execution, and communication of results. We propose new programs for the training of mentors and for monitoring of both mentor and mentee progress. We leverage the T32 support by integrating these activities and learning opportunities throughout each student’s graduate career, and not just during the 1-year T32-appointment period. In addition, we extend T32-sponsored training opportunities to others by making the majority of proposed activities available to all students, regardless of training-grant eligibility. Importantly, we have established a long-term working relationship with Dr. Cathleen Cerosaletti, who specializes in STEM Evaluation and Research and is faculty in the University of Rochester Warner School of Education. Cerosaletti has put in place modern assessment protocols and metrics so that we can evolve and improve student training and mentoring in real-time. The proposed next phase of our Training Program will build on the initial funded period, as well as the 15 years of experience garnered from this previously T32-funded Training Program.

NIH Research Projects · FY 2025 · 2020-07

PROJECT SUMMARY/ABSTRACT Extracellular pH is a highly dynamic and ubiquitous signal and many cell types exhibit robust electrophysiological responses upon extracellular acidification, particularly in the nervous system. Acid-sensing ion channels (ASICs) are thought to mediate the majority of these responses since various ASIC subunits are expressed at high levels in many neuronal types and genetic ablation of ASIC subunits dramatically reduces acid-evoked responses. Consequently, ASICs are vital players in numerous physiological and pathophysiological circumstances including ischemic stroke, basal neurotransmission, synaptic plasticity, pain, inflammation and various cancers. These myriad roles of ASICs have motivated structural and biophysical investigation, leading to crystal or cryo-EM structures of chicken ASIC1 in the resting, toxin-stabilized open and desensitized states. Combining these structural efforts with functional experiments have led to a working model where protonation of key acidic residues in the extracellular domain's acidic pocket leads to global rearrangements driving activation and desensitization. In recent years we have made key insights into the molecular determinants of the activation and desensitization processes at individual subunits. Yet we lack a clear understanding of how these subunits work together. Are conformational changes at one subunit sufficient to desensitize ASICs? Does conformational change in one subunit co-operatively influence the adjacent subunits? We will address these core questions by measuring functional properties of channels with defined stoichiometry. In addition, we will employ powerful next-generation fluorometry approaches and single molecule FRET studies. Finally, to gain insight into the pH stimulus encountered by ASICs we will use protein engineering to measure physiological pH changes. Taken together, these proposed experiments will provide insight into essential unanswered questions in ASIC biology while developing novel tools of broad applicability.

NIH Research Projects · FY 2024 · 2020-07

Project Summary/Abstract: This proposal represents a five-year research career development program focused on the study of longitudinal cognitive outcomes among children and adolescents with HIV in Zambia. The outlined proposal builds on the candidate’s prior research and experience, and will introduce the candidate to new skills that will be shared by the mentorship team led by Dr. Gretchen Birbeck, an expert in neuroepidemiology and clinical trials in resource-limited settings. The proposed training and mentored research will enable the candidate to transition to an independent research career focused on neurologic complications of HIV. Cognitive impairment is common in children with Human Immunodeficiency Virus (HIV) in low-resource settings, affecting up to 50% of perinatally-infected children in Sub-Saharan Africa. In children with HIV receiving Antiretroviral Therapy (ART), opportunistic infections and severe HIV-associated progressive encephalopathy have become less common, but more subtle forms of cognitive impairment have increased in prevalence. The foundation for this proposal is based on research conducted by the candidate as part of the HIV-associated Neurocognitive Disorders in Zambia (HANDZ) study, in which 208 children and adolescents with HIV and 208 HIV-exposed uninfected controls were recruited, and clinical risk factors and biomarkers for cognitive impairment were evaluated. In the HANDZ study, we found that serum markers produced by activated platelets and pro- inflammatory monocytes associated with depression, cerebrovascular disease, and cognitive impairment, suggesting that platelet-monocyte complexes (PMCs) may be key drivers in HIV-associated cognitive impairment. In the proposed project, the population recruited as part of HANDZ will be followed longitudinally for a total of five years, and an additional HIV-unexposed uninfected control group will be recruited. The aims of this proposal include 1) To evaluate whether PMCs and pro-inflammatory monocytes predict depression and cognitive outcomes in ART-treated children and adolescents with HIV in Zambia 2) To assess whether PMCs and pro-inflammatory monocytes are associated with cerebrovascular disease in ART-treated children and adolescents with HIV and 3) To develop a comprehensive predictive model of cognitive change in children with HIV incorporating clinical characteristics, plasma biomarkers, and imaging biomarkers. The short- term goal of this application is to 1) Train the applicant through mentored research 2) Identify a subpopulation of children and adolescents with HIV at high risk of cognitive decline and 3) From clinical profiles, plasma biomarkers and imaging characteristics, identify factors associated with the greatest effect on cognitive outcomes that can be targeted in future intervention studies. The long-term impact will include setting the stage for clinical trials of interventions to prevent or treat HIV-associated neurocognitive disorders in children and adolescents.

NIH Research Projects · FY 2025 · 2020-06

Project Summary: The overarching goal of this proposal, submitted in response to RFA-CA-19-035, is to evaluate if an aging- sensitive survivorship intervention improves outcomes valued by older adults and their caregivers during the transition into survivorship from curative-intent chemotherapy. This proposal is important because by 2040, 73% of survivors will be aged 65+ and almost 50% will be aged 75+. Unfortunately, aging- related conditions (e.g., physical and cognitive function impairments) are not addressed routinely in survivorship care. Preliminary research by all multiple principal investigators (MPIs: Mohile, Janelsins, Mustian) suggests that a Geriatric Evaluation and Management (GEM) intervention is effective for surveilling, triaging and managing physical and cognitive impairments, improving patient and caregiver satisfaction, and fostering communication about aging-related conditions during chemotherapy in older cancer patients and their caregivers. Preliminary research by MPIs also suggests that a Survivorship Health Promotion program is effective for improving physical function among older survivors after chemotherapy. Our MPI team has shown that GEM and Survivorship Health Promotion are feasible to implement in older patients, survivors and caregivers in nationwide samples recruited via the University of Rochester Cancer Center (URCC) NCI Community Oncology Research Program (NCORP) Research Base network. To fill existing empirical gaps in survivorship care for older survivors and caregivers, we created a novel intervention called Survivorship-GEM by combining these two very promising and synergistic programs. Survivorship-GEM is directed by oncology advanced practice providers (APPs), because they routinely direct care for survivors in the community. We propose to conduct a two-arm cluster randomized trial comparing the efficacy of our novel Survivorship-GEM intervention to usual care for improving physical and cognitive function, satisfaction with care, completion of referral appointments, and hospitalizations among older survivors. We will also examine the effect of Survivorship-GEM on oncology APP communication with primary care providers and on caregiver distress and satisfaction with care. We will randomize 30 NCORP community oncology practices to two arms: 1) Survivorship-GEM or 2) usual care. Survivors aged 65+ (n=720) and caregivers (if available, estimated n=500) will complete baseline assessments at the end of curative-intent chemotherapy for a solid tumor malignancy with follow-ups at 6 and 12 months. Our uniquely qualified, multidisciplinary team includes expertise in geriatrics, clinical trials, nursing, primary care, behavioral oncology, rehabilitation, health disparities, biostatistics, and implementation science. The team also benefits from collaborations with the Cancer and Aging Research Group Advisory Board and the SCOREboard patient advocate group. The APP-directed Survivorship-GEM intervention is highly innovative and has tremendous potential to improve outcomes in older survivors and caregivers by surveilling, triaging and managing the effects of chemotherapy and by fostering health promotion.

NIH Research Projects · FY 2026 · 2020-05

The Rochester Musculoskeletal (ROCMSK) T32 Training Program, administered by the University of Rochester's Center for Musculoskeletal Research (CMSR), is committed to training future generations of innovative, responsible leaders in musculoskeletal science. Building on a legacy of excellence and over $28M in current funding of 31 interdisciplinary faculty mentors, the ROCMSK's Training Program renewal proposal offers a dynamic training experience for five pre-doctoral trainees. Through mentorship and rigorous scientific training, trainees will acquire the skills essential for independent research careers in musculoskeletal science. The program's emphasis on scientific communication, wellness, and a supportive academic environment will cultivate independent thinkers and collaborative problem solvers. The program's commitment to translational research will be enhanced through innovative clinical shadowing experiences and networking travel sabbaticals, providing trainees with invaluable insights into the real-world impact of their research findings. ROCMSK aims to: 1) Provide a rigorous foundation in trans-disciplinary musculoskeletal research, emphasizing cutting-edge methodologies, ethical conduct, and data-driven discovery. Trainees will engage in hands-on research rotations and thesis/dissertation projects under the mentorship of accomplished faculty. 2) Nurture critical thinking, independence, and a deep understanding of musculoskeletal health. Trainees will benefit from clinical shadowing, networking opportunities, and collaborations with academic and industry partners. 3) Leverage institutional resources to enhance scientific collaboration and research excellence. 4) Empower trainees to excel in scientific communication. Structured training, including student-led grant-writing groups and mock NIH study sections, will prepare trainees for successful research careers. 5) Promote trainee wellness and a supportive academic environment. Collaboration with the institutional Learner Life and Wellness initiative will ensure holistic well-being, fostering resilience and collaboration. 6) Rigorously evaluate program effectiveness. Annual assessments through focus groups, interviews, and surveys, facilitated by the Center for Professional Development and Education Reform, will drive continuous improvement. With its national reputation, extensive collaborations, and structured training program, ROCMSK is well-positioned to meet the growing demand for training skilled musculoskeletal scientists.

NIH Research Projects · FY 2025 · 2020-05

ABSTRACT Rates of adolescent vaping are increasing rapidly. Current high school student use of electronic vaping products (EVPs) rose from 1.5% in 2011 to 20.8% in 2018 – an increase from 220,000 to 3.05 million adolescent users. Vaping is associated with respiratory symptoms, and exposure to nicotine can act as a `gateway' to other drug use. Effective, school-based interventions are urgently needed to protect adolescents from initiating or continuing use of EVPs. A recent US Surgeon General's report identified no school or community based prevention program that reduces vaping behaviors among youth. This proposal takes advantage of a state-supported prevention initiative to test the efficacy of Above the Influence of Vaping (ATI- V). ATI-V trains peer nominated 8th-9th grade Peer Leader, and adult advisors. Peer Leaders learn skills and implement school-wide prevention campaigns informed by communication science. Preliminary data show that after training approximately 15% of 8th graders as Peer Leaders, who implemented school-wide campaigns, students who were friends of Peer leader had reduced vaping intentions and vaping behaviors 2nd semester of 8th grade. New York State has provided funds to support schools to implement ATI-V but no funds for efficacy research. With support from New York State and a strong team of investigators, our project has three aims: Aim 1. Efficacy. The primary aim of this study is to determine ATI-V impact in preventing vaping use (past 30 days any vaping, nicotine vaping, and regular use). Using an RCT design, 20 schools will be assigned to (a) immediate ATI-V, or (b) wait-list for ATI-V training after 24 months. Approximately 3,800 8th graders will be enrolled and followed for assessments in fall 8th grade, spring 8th grade, spring 9th grade, and mid-year 10th grade. We will test for which students ATI-V is most effective and in what school contexts (school climate). Aim 2. Mechanism. The second aim of this study to test the hypothesized mechanisms of ATI-V impact. To accomplish this aim we will conduct statistical analyses of a mediation model to determine (a) whether ATI-V improves students' perceptions that vaping is unacceptable to their peers (anti-vaping norms), connections to supportive adults to address EVP concerns, and social influence of non-vaping students; and (b) whether the impact of ATI-V on reduced vaping behavior is mediated by these improvements. Aim 3. Implementation (Exploratory). Our exploratory aim is to identify implementation barriers and facilitators by gathering qualitative data (observations, semi-structured interviews) from staff and students from a subset of high and low implementing schools. The purpose is to identify what implementation strategies and supports are needed for future schools to be successful in implementing ATI-V, if warranted by the study findings. If study hypotheses are supported, this study will provide, to our knowledge, the first evidence of a school-based prevention intervention that reduces adolescent vaping behaviors.

NIH Research Projects · FY 2026 · 2020-04

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA-DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child’s changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.

NIH Research Projects · FY 2026 · 2020-04

Project Summary/Abstract Staphylococcus aureus (S. aureus) has been strongly implicated as a causal factor in pathogenesis of atopic dermatitis (AD) since the 1970s, and is further supported by publications demonstrating S. aureus skin colonization precedes AD onset. ADRN studies found that 50% of AD subjects are colonized and this AD phenotype is associated with greater epidermal barrier dysfunction, type 2 immunity, disease severity and remarkable alterations in the skin microbiome (increased S. aureus relative abundance and reduced abundance of the commensal bacteria, Cutibacterium acnes (C. acnes). Additionally, S. aureus-colonized AD subjects are more likely to develop a severe viral condition, called eczema herpeticum. An even more serious condition is eczema vaccinatum, caused by exposure to vaccinia virus (smallpox vaccination), which has a fatality rate as high as 30%. In an effort to explain this, we found discovered that epidermal exposure to a highly virulent S. aureus strain (USA300), commonly found on AD subjects, markedly enhances its susceptibility to vaccinia virus. Collectively, these observations support our hypothesis that S. aureus may be a key driver of disease severity and response to systemic treatments (Aim 1) as well as serious viral complications (Aim 2). Determining what role C. acnes, the most abundant commensal skin bacteria, plays in suppressing S. aureus will be the focus of studies outlined in Aim 3. These studies will leverage the wealth of deeply-phenotyped AD subjects and their biospecimens from previous ADRN studies (ADRN02-Registry, ADRN06-ADEH and ADRN09-Dupilumab) and those enrolled into URMCs Longitudinal ‘Real-World’ AD Study. The Aims demonstrate how the focus is first on the systemic features of S. aureus colonization (e.g. macro level; Aim 1) and moves to the “epidermal (host) – microbiome” interaction (Aim 2) and ultimately to the microbe-microbe interaction at the skin surface (e.g. micro level; Aim 3).

NIH Research Projects · FY 2026 · 2020-04

Erythropoiesis is a finely orchestrated process that involves generating a ~2.5 million red blood cells per second to maintain homeostasis and prevent anemia. RNA Polymerase II (RNAPII) pausing is a highly regulated and fundamental mechanism of transcriptional regulation, whereby transcription is initiated, but pauses 30-60 bp downstream of the transcription start site. Release of paused RNAPII into active elongation requires phosphorylation of RNAPII and associated inhibitory factors by positive transcription elongation factor beta (pTEFb). Our group has shown that regulation of RNAPII activity is an essential determinant of erythroid cell function, with central roles in the regulation of gene expression and cell cycle progression. HEXIM1 is a key regulator of pTEFb activity that can enforce pausing or facilitate pause release, depending on genomic context. HEXIM1 is essential for erythropoiesis, and promotes erythroid proliferation and the expression of GATA1-target genes. Despite its importance, fundamental questions remain regarding the mechanisms by which HEXIM1 regulates RNAPII activity and promotes erythroid gene expression. HEXIM1 is classically thought of as a transcriptional repressor, which enforces RNAPII pausing by sequestering pTEFb in the 7SK complex. Data from our group and others suggests the HEXIM1-pTEFb-7sk complex can be targeted to specific genes, where it is available for “onsite” release of pTEFb, facilitating pause release. In Aim 1, we will address the hypothesis that delivery of pTEFb to specific genes by HEXIM1 and the 7SK Complex is essential for both steady state and stress erythropoiesis. RNAPII pausing is regulated by cell type- and maturation stage-specific transcription factors and signaling pathways. Early erythropoiesis is comprised of the differentiation of multipotent progenitors to erythroid progenitors, while terminal maturation consists of the maturation of proerythroblasts through several intermediates into orthochromatic erythroblasts that ultimately enucleate. In contrast to terminally maturing cells, erythroid progenitors have the ability to undergo self-renewal divisions, and to expand in response to anemic stress. HEXIM1 is expressed in erythroid progenitors and upregulated in terminally maturing cells. Other key regulators of pTEFb, including Bromodomain Protein 4 (BRD4), and the Mediator Complex are highly expressed in erythroid progenitors and down regulated during terminal maturation. Erythroid progenitors also have higher levels of RNAPII than terminally maturing cells. These data suggest that the transcriptional environment of erythroid progenitors is distinct from that of terminally maturing cells. In Aim2, we will address the hypothesis that RNAPII activity is regulated in a maturation stage-specific manner. The proposed studies will provide novel insights into the mechanisms that govern normal and perturbed erythropoiesis, and have the potential to identify novel therapeutic targets for inherited and acquired anemias.

NIH Research Projects · FY 2026 · 2020-02

Human Cytomegalovirus (HCMV) is a major cause of congenital birth defects and causes severe disease in a wide variety of immunosuppressed patient populations. Current anti-HCMV therapeutics suffer from toxicity, poor bioavailability, and the emergence of drug resistance, thus highlighting the need for novel anti-viral development strategies. Viruses rely on cellular metabolic resources for productive infection. Our laboratory studies the interface between viral gene products and cellular proteins involved in metabolic regulation to identify points of potential therapeutic intervention. We find that the HCMV UL38 protein induces mitochondrial respiration, which is critical for HCMV replication. In addition, we have found that two cellular mitochondrial regulatory activities are important for HCMV infection. One of these is EGLN1, a regulatory prolyl hydroxylase, the activity of which we find is critical for HCMV-mediated activation of mitochondrial respiration and successful infection. The second is a mitochondrial CLPP protease that controls protein turnover in the mitochondria, and upon agonist addition, inhibits HCMV replication. The proposed research will elucidate the mechanisms through which UL38 and EGLN1 activate mitochondria (Aim 1) and how EGLN1 contributes to productive infection (Aim 2). We will also elucidate the mechanisms through which CLPP activation inhibits viral infection (Aim 3). Collectively, our proposed research will explore the mechanisms through which viral and cellular factors modulate metabolism and mitochondrial physiology to determine infectious outcomes. Targeting these factors could pave the way for therapeutic development to block HCMV-associated pathogenesis.

NIH Research Projects · FY 2026 · 2020-02

Neurons integrate multiple inputs and coordinate a series of molecular events to drive cellular function. During neurotransmission, electrical depolarization at the pre-synaptic axon is transduced to chemical signals that affect post-synaptic dendrites. Neurons depend on mitochondrial function for survival. At the center of mitochondrial function is the protonmotive force (PMF), an electrochemical proton gradient that coordinates metabolic signaling and energetic responses. The PMF acts like a ‘bioenergetic battery’ and the stored electrical energy is used to uptake metabolites, make ATP, alter reactive oxygen species production, and buffer cellular calcium signaling. The PMF is dynamic and fluctuates in biology to drive cellular differentiation and autophagy, while the loss of PMF is associated with neurodegeneration and cell death. Maintaining PMF is required for neuronal function, and the neuronal architecture offer unique cellular environments. Distinct neuronal regions have unique biological constraints and mitochondrial energetic demands. Likewise, mitochondrial morphology and function are also specialized in a compartment-dependent manner. How neurons fuel cellular processes and how individual mitochondrial populations modulate energetics in each neuronal compartment remains poorly understood in part due to the lack of tools offering cell-specific and spatiotemporal control of the PMF. This R01 renewal addresses this gap in the field by leveraging discoveries from the previous funding period, where we developed a novel optogenetic approach to independently control, both spatially and temporally, the PMF in vivo. The neuronal cell membrane potential integrates and regulates numerous facets of neuronal signaling and health. Much like the neuronal membrane potential, we propose that the mitochondrial PMF acts as a central integrator to transduce signaling and power a wide array of cellular pathways and functions. We hypothesize that neuronal responses to mitochondrial energetics are highly dependent on the timing, duration, and location of the mitochondrial perturbation. Controlling the PMF has been a long-standing challenge in mitochondrial biology. Here, we propose to use light to increase or decrease the PMF in distinct neuronal compartments and dissect the effects on neuronal function. Accumulating evidence demonstrates that altering energy status has wide ranging effects on neuronal function. We will determine the spatiotemporal tenets defining mitochondrial PMF signaling across neuronal compartments and how these signals affect neuronal activity and in vivo behavior. Addressing the neuropathologic heterogeneity of mitochondrial function in neurons will advance the field and define novel, targeted approaches to guide therapeutic strategies targeting neurodegeneration.

NIH Research Projects · FY 2026 · 2019-12

The Vaccine and Treatment Evaluation Units (VTEUs) are a critical resource for the NIAID Infectious Diseases Clinical Research Consortium to conduct clinical research and trials to evaluate vaccines, preventive biologics, therapeutics, diagnostics, predictive markers, and devices for the treatment and prevention of infectious diseases in people of all ages and risk categories. The VTEU network sites must flexible and respond to emerging threats and changing NIAID priorities. To this end, the University of Rochester VTEU (UR VTEU) will collaborate with NIAID and the VTEU leadership group (VTEU LG) to address and prioritize initiatives for infectious diseases such as respiratory, enteric, sexually transmitted infections and antibiotic resistant organisms as well as maintain flexibility to switch focus to emerging threats as the need arises. The University of Rochester is fortunate to enjoy a community with a very positive attitude towards clinical research and collaborative relationships between the major healthcare providers in the city providing access to all the hospitals, clinics and practices in the area. The UR VTEU offers a very experienced administrative and clinical group with a proven track record of successful multicenter clinical trial work. With the support of the VTEU LG, the UR VTEU will be well positioned to develop as well as implement concepts and projects that address important NIAID priorities and formulate best practices, efficiencies and standard operating procedures among VTEU sites. UR VTEU investigators have expertise in adult and pediatric clinical research as well as recruitment of vulnerable populations into clinical trials and thus can anticipate successful recruitment of young and older adults, infants, young children and adolescents, and pregnant women. Additionally, the close relationship of the Monroe County Health Department with the University provides access to patients with sexually transmitted diseases for study participation. We will provide capacity to perform phase 1-3 clinical trials and pharmacokinetic studies as well as surge capacity in terms of personnel and clinical research sites to rapidly respond to urgent NIAID demands. Importantly, our investigators have experience conducting challenge and isolation studies and can provide VTEU facilities for such projects. Our research laboratory expertise will provide the VTEU network with a variety of state of the art technologies to interrogate the host response to infection and immunization as well as develop a deeper understanding of pathogenesis for many infectious diseases. Specifically, core faculty have expertise in a wide range of novel immunologic assays as well as transcriptional and microbiome analysis. In addition, the UR VTEU will provide research opportunities and education for junior faculty to train the next generation of physician scientists. All clinical trials will adhere to NIAID/NIH requirements and comply with Good Clinical Practice. In summary, the UR VTEU site will offer an enthusiastic and diverse group of investigators with a track record of participating in collaborative research and the necessary scientific, clinical, administrative and organizational structure to support NIAID activities.

NIH Research Projects · FY 2024 · 2019-09

PROJECT SUMMARY / ABSTRACT The NIH's HEAL Initiative aims to support collaboration between clinical research experts in academia and industry to accelerate the development of highly efficacious, non-addictive analgesics for well-defined chronic pain syndromes. The University of Rochester (UR), and its proposed leadership for the UR Hub and Spokes within Early Phase Pain Investigation Clinical Network (EPPIC-Net), have extensive expertise in designing and conducting analgesic trials of small molecule drugs, devices, and biologics. These trials have included both investigator-initiated phase 2 trials and participation multi-site industry-sponsored clinical trials with a main focus on well-phenotyped chronic low back pain (CLBP) syndromes, which is one of the top priorities for the NIH's proposed EPPIC-Net. Currently, there are thirteen committed potential protocol PIs at the UR Hub and four Spokes. Together these PIs have the ability to recruit subjects with a broad range of pain conditions from the following subspecialties: anesthesiology, dentistry, emergency medicine, gastroenterology, gynecology, neurology, neurosurgery, oncology, orthopedics, pediatrics, rheumatology, and urology. Each of these committed potential PIs has extensive clinical trial experience and existing infrastructure to support patient recruitment and retention, timely and accurate data entry, and regulatory documentation. In addition, the proposed UR-EPPIC-Net Collaboration Core is well equipped to recruit additional Spoke sites using the members' broad, regional and national network of analgesic researchers. UR has multiple resources to promote efficient subject recruitment and trial quality, including (1) the UR Clinical and Translational Science Institute's Trial Hub Liaison Team and Recruitment Unit, Community Engagement Studios, and Clinical Research Center; (2) the Practice-Based Research Network of regional primary care practices; and (3) the Office for Human Subject Protection – Quality improvement division. The UR also has multiple resources to support deep phenotyping of chronic pain patients, including (1) the Neuroimaging Core, (2) the Neuromuscular Pathology Laboratory, (3) quantitative sensory testing expertise, and (4) the Physical Exercise Activity Kinesiology Laboratory. This proposal outlines a leadership and oversight infrastructure to allow for the nimble, efficient, and high integrity implementation of EPPIC-Net clinical trials. Institutional leadership commitments include the use of a central Institutional Review Board (IRB) and the adoption and implementation of master trial agreements templates. As a result, the proposed UR-EPPIC-Net Hub and Spokes are well positioned to work with the EPPIC-Net Data and Clinical Coordination Centers to design and rapidly conduct phase II therapeutic trials across a broad range of pain conditions, and to set new standards for conception, implementation, and dissemination of pain research.

NIH Research Projects · FY 2025 · 2019-08

ABSTRACT Respiratory tract disease is surpassed only by mental health as the top-most costly and frequent medical condition affecting our children and resulting in adult disease with perinatal-pediatric origins. "The overall goal of LungMAP is to build a comprehensive molecular and cellular atlas of the human lung to serve as a reference platform to better understand both normal biology and disease pathobiology, and to identify critical cellular components, molecular pathways, and novel therapeutic targets in lung disease." Discovery of meaningful treatments for these disorders is limited by the rarity of access to sufficient normal and diseased human lung for high resolution, multi-scale study. Having, as the original Human Tissue Core (HTC) for the Molecular Atlas of Lung Development Program (LungMAP), created the BioRepository for INvestigation of Diseases of the Lung (BRINDL), encouraged and facilitated use of these biospecimens in highly productive collaborations between LungMAP HTC and RCs, developed new techniques for preserving and assaying these high-quality human tissues, and distributed biospecimens to the research community, the University of Rochester Medical Center (URMC) submits this renewal application in response to single source RFA-HL-24-015 to continue to serve as the HTC for LungMAP Phase 3. Begun as a repository for normal pediatric development, LungMAP II extended to include pediatric rare diseases including bronchopulmonary dysplasia, chILD, pulmonary hypoplasia and the more common disease, asthma. In Phase III, our proposal closely follows the Notice of Funding Opportunity that summarizes the "main goal of the HTC in Phase 3 is to catalog, store, and distribute human lung samples from the current LungMAP repository and from the LungMAP Research Centers (RCs)." The HTC will, while complying with current NIH and regulatory policies, selectively add pediatric rare lung diseases and certain healthy pediatric cases, enhance diversity in ethnicity and ancestry, assist Research Centers in acquiring diseases of their expertise, organize all case metadata within BRINDL, improve the BRINDL specimen and data management and distribution system (https://brindl.urmc.rochester.edu), integrate with the DCC portal system to improve user experience, and prepare to transition the biorepository at LungMAP sunset.

NIH Research Projects · FY 2026 · 2019-08

Microbes employ diverse defense systems to provide protection from viruses, and studying these systems is important for understanding immune system evolution, phage therapy, and the discovery of new molecular tools such as CRISPR-Cas systems. While it’s broadly thought that CRISPR-Cas systems work exclusively by degrading nucleic acids, we’ve recently shown that membrane perturbation by accessory proteins (e.g., Csx28) are an unappreciated aspect of CRISPR-Cas’s mechanism of action. However, the molecular mechanisms of how proteins like Csx28 function are unknown. The goal of my research is to understand how CRISPR-Cas systems and their membrane-associated proteins function together to enhance anti-viral defense with an eye towards the discovery of new tools. This proposal focuses on addressing the following gaps: 1) What is the mechanistic and structural details of Csx28 activation by Cas13? We recently discovered that the RNA-targeting Cas enzyme Cas13 is communicating with membrane pore protein Csx28, to mount a robust anti-viral immune response, however we still don’t understand what the precise molecular mechanism involved. Our preliminary data indicate that Cas13 generated RNA cleavage products are acting as ligands to gate Csx28 channel activity. We will use RNA sequencing and membrane biophysics approaches to determine the precise RNA ligands modulating Csx28 activity and how these ligands affect gating of the Csx28 pore, respectively. These experiments will shed light on the molecular details of fascinating anti-phage synergy between Cas13 and Csx28 and provide a clear path for technology development. 2) Do Csx28-like proteins have roles in anti-viral defense outside of CRISPR systems? With our structural studies of Csx28 coupled with the recent advances in structure prediction databases, we discovered that Csx28 shares very close structural similarity to a family of hypothetical proteins that reside in potentially new immune systems. We hypothesize that these Csx28-like proteins are employed to modulate membrane function during viral infection, however no experimental studies have been done. We will use similar genetic, biochemical, and structural approaches to our previous work on Csx28 to study these putative membrane proteins. 3) How does Cas13 associated protein Csx27 modulate antiphage defense? Csx27 is a predicted transmembrane CRISPR accessory gene that resides within a subset of Cas13b containing loci. Csx27 has recently been shown to work with Cas13b from to modulate anti-phage defense, however the mechanism is not understood. Our preliminary data suggest that Csx27, while bearing no similarity to Csx28, also acts as a membrane pore and activation by Cas13b results in a similar loss of membrane potential, and a muted metabolism, however more work needs to be done to understand the details these of effects. We will use a similar set of genetic, biochemical, and structural approaches that were successful previously for Csx28 with the goal of understanding of Csx27’s role in Cas13b antiphage defense, and to pave the way for downstream technology e.g., potential applications that tie RNA expression levels to the modulation of membrane behavior.

NIH Research Projects · FY 2026 · 2019-07

T cell migration and cardiovascular toxicity in immunotherapy. Adoptive T-cell transfer therapy has emerged as a promising therapeutic option with complete and durable responses in several disease conditions such as viral infection, autoimmune disease, atherosclerosis, and cancer. However, severe immune-mediated cardiovascular toxicities caused by cytokine release syndrome (CRS) are observed in most patients, and these adverse reactions remain a significant obstacle in developing effective and safe therapies. In studies conducted in the previous cycle of this grant, we showed that in vitro activated T cells are immediately sequestered at the perivascular space of non-specific tissue sites after the intravascular infusion. This non-specific accumulation is mediated by aberrant LFA-1 activation and may be closely associated with impaired T cell functions and increased risk of severe CRS and cardiovascular toxicity. In this study, we will build on these data and identify key mediators that can control the tissue-specific migration of adoptively transferred T cells and harness these mechanisms to increase the efficacy of T cell immunotherapy while reducing the risks associated with cardiovascular toxicity. To this end, we used (1) in vivo intravital multi- photon microscopy to determine the fate of the adoptively transferred therapeutic T cells after infusion and performed (2) an in vivo CRISPR–Cas9 knockout screen and (3) a high-throughput pharmacologic screening to discover key T cell-intrinsic mechanisms that regulate therapeutic CD8 T cell migration to targeted tissue sites. We will, (Aim 1) determine how clinically manufactured T cells interact with the endothelium in non-specific tissues after infusion and impact vascular barrier functions, (Aim 2) determine the molecular mechanisms that can minimize non-specific sequestration but improve specific T cell migration toward the target tissue site, and (Aim 3) determine whether the newly discovered T cell homing mechanisms (Aim 1 and Aim 2) are associated with therapeutic outcomes and the cardiovascular risk in patients. These studies will combine differential perturbations of novel mechanisms that regulate activated T cell migration in in vivo mouse models, state-of-the- art intravital multiphoton imaging, high-resolution pathway screenings, and assay analyses defining vascular inflammatory responses.

NIH Research Projects · FY 2025 · 2019-07

This is a fourth competing renewal of the Clinical and Translational Cancer Control Research Training Program (CCRTP) led by Drs. Michelle Janelsins, Luke Peppone, and Gary Morrow of the University of Rochester (UR) and Wilmot Cancer Institute (WCI). The primary aim of the 2- to 3-year CCRTP is to provide PhD and MD trainees with the tools and experiences necessary to establish careers as outstanding independent investigators in cancer control research. This program fills an unmet need to train the next generation of cancer control investigators. As improvements in cancer treatments increase survival rates, there are 20 million cancer survivors; these survivors continue to experience ongoing side effects that negatively impact quality of life. Thus, there is a greater need to better understand the numerous debilitating side effects of cancer treatment and develop interventions. The program combines didactic and “hands-on” research training activities. We focus on four core training areas (i.e., clinical trials, translational science, biostatistics, and professional development), along with specialty training areas of choice in psychological interventions, exercise oncology, geriatric oncology, and nutrition. Dr. Peppone, a former graduate of the CCRTP, formally joins Drs. Janelsins and Morrow as MPI to enhance the nutritional and natural product component of the CCRTP, providing synergy with Drs. Janelsins and Morrow’s expertise in clinical trials. For example, a number of recent trainees have focused on interventions such as Mediterranean diet, time-restricted eating, and fucoidan supplementation to alleviate side effects. Drs. Janelsins, Peppone, and Morrow are joined by 20 multidisciplinary, outstanding, experienced R01-funded mentors and 5 junior co-mentors with NCI K Awards from 10 academic departments, and exceptional infrastructure support from the NCI-funded University of Rochester Cancer Center Community Oncology Research Program (URCC NCORP) Research Base, among others, as well as unparalleled institutional support to the Division of Supportive Care in Cancer specifically for trainees in the program to conduct and publish independent analyses and develop their own independent clinical and translational research projects. These research experiences are complemented by completion of a Master’s (MS or MPH) degree focused in clinical investigation, epidemiology, translational research, health services, or data science. For our last 5 classes, 78 applicants have been evaluated; 12 outstanding candidates were selected for on-site interviews; all accepted and matriculated. They have produced 143 unique manuscripts, obtained several outstanding research awards, and earned K-level research funding and tenure-track faculty positions. A majority (90%) of our trainees are still in academic cancer research careers at Assistant (9), Associate (24), and Full (5) Professor level; many are now leaders as directors of major programs within cancer centers. Our next renewal will continue to build upon this momentum with new innovations and retaining pearls of success with our ultimate goal of improving the lives of patients with cancer.

NIH Research Projects · FY 2025 · 2019-07

Loss of hair-cell innervation by auditory-nerve fibers is a prevalent cochlear pathology in humans associated with aging and sound overexposure, that does not impact audiometric thresholds in quiet. Called cochlear synaptopathy, this inner-ear problem is widely expected to cause “hidden” hearing difficulties such as impaired speech perception in noise. However, evidence that synaptopathy causes hidden hearing loss remains controversial despite over a decade of intensifying research on the topic. Animal studies are well positioned to advance this field because the approach allows direct induction of synaptopathy and targeted neural recordings to identify underlying mechanisms. However, only a few studies have leveraged this approach. The proposed study will clarify specific aspects of perception impacted by synaptopathy and underlying mechanisms using animal behavioral experiments, auditory-nerve fiber recordings, and midbrain-neural recordings in actively behaving animals. Experiments are conducted in budgerigars (parakeet) based on adaptability of this species to operant-conditioning experiments and behavioral sensitivity similar to humans on many simple and complex hearing tasks. Furthermore, accumulating evidence highlights conserved auditory processing mechanisms between birds and mammals at peripheral and central levels. We test the novel hypothesis that synaptopathy impairs perception of brief acoustic cues due to amplification of neural onset responses, a nominal “gain of function” that we predict will degrade neural resolution of short signals due to response saturation. This hypothesis is a significant departure from conventional theories based on low spontaneous-rate fiber loss, which was not confirmed in a recent mouse study, and has direct relevance to speech communication for which auditory analysis of short time periods is often critical. Furthermore, the hypothesis is supported by recent auditory-nerve studies, and new preliminary data in budgerigars showing that synaptopathy selectively degrades detection of tone bursts presented at the onset of a noise masker. Synaptopathy is induced with kainic acid and validated histologically using established methodology. Additional Aim-1 studies extend behavioral experiments into the critical realm of speech using synthesized consonants. Aim-2 experiments use single-fiber auditory-nerve recordings to establish a firm baseline knowledge of how synaptopathy impacts peripheral encoding and temporal dynamics. Aim 3 uses neural recordings from a key midbrain processing center to determine the changes in central processing with synaptopathy; recordings from actively behaving animals are analyzed with neural decision-variable correlations for maximum insight into neural bases of normal and impaired perception. The detailed knowledge of specific perceptual deficits and underlying changes in peripheral/central encoding provided by this work will help guide the development of new public-health strategies to address cochlear synaptopathy. Ultimately, the proposed project holds promise to expand and potentially redefine current thinking on synaptopathy and hidden hearing loss.

NIH Research Projects · FY 2024 · 2019-07

PROJECT SUMMARY Cancer-related cognitive impairment (CRCI) is a troublesome side effect reducing overall daily functioning for many breast cancer patients undergoing chemotherapy. In Dr. Janelsins’ NCI-funded nationwide, prospective cohort study, 45% of breast cancer patients report clinically significant post-chemotherapy (URCC10055; N=945); this is one of the largest studies of CRCI to date and the only one we are aware of in community oncology clinics. CRCI may also persist long-term; however, large studies incorporating pre-chemotherapy time-points are needed to clearly elucidate long-term trajectories of CRCI. In URCC10055, Dr. Janelsins and colleagues used two tests that address specific cognitive functions: 1) the Delayed Match to Sample (DMS) task—a visual working memory test with sensitivity to the prefrontal cortex dysfunction and with analogous features to the delayed spatial alternation test used in her CRCI mouse model, and 2) the Rapid Visual Processing Test (RVP)—a sustained attention test with sensitivity to parietal and frontal lobe dysfunction. With both the DMS and RVP tests, there was a significant decline in breast cancer patients receiving adjuvant chemotherapy from pre- to 6 months post-chemotherapy compared to age-matched controls assessed at the same times (N=943). By comparison, the standard neuropsychological tests did not reveal significant differences at this time-point suggesting they may lack sensitivity for assessing long-term decline. We also present preliminary data that the inflammatory pathways may be related to lower DMS scores. Based on our preclinical data, and literature of others, we will also add a new learning test to precisely address hippocampal function, the Paired Associated Learning (PAL) test. Our aims are to conduct a comprehensive assessment of long-term CRCI in specific cognitive functions of visual working memory (DMS; primary aim; Aim 1a), sustained attention (RVP; Aim 1b) and new learning (PAL; Aim 1c) at 7 and 9 years post-chemotherapy in breast cancer patients compared to controls, assessing specific factors leading to cognitive decline, and to assess the impact of long-term CRCI with these measures on daily function (Aim 2), inflammation (Aim 3), and relationship to other cognitive measures (standard neuropsychological, self-report; Aim 4). In order to address these innovative aims, we will leverage URCC10055 to collect new 7- and 9-year data on 450 breast cancer patients (survivors) and 300 controls. These time-points coincide with gaps in the literature in evaluating longitudinal, long-term CRCI and these are the time-points available during the funding period. In order to evaluate long-term longitudinal CRCI, we will also leverage the existing URCC10055 data (pre-chemotherapy, post-chemotherapy, and 6 months follow-up). This proposal will fill critical gaps in the field in our understanding of longitudinal long-term effects of CRCI from prior to chemotherapy, biologic processes involved, and impact on overall daily functioning. These cognitive measures could provide practical yet CRCI- specific screening methods in busy oncology clinics and inform future mechanistic and CRCI intervention trials.

NIH Research Projects · FY 2026 · 2019-03

PROJECT SUMMARY The University of Rochester, Wilmot Cancer Institute is ideally suited to achieve the goals of the NCI National Clinical Trials Network (NCTN) as a Lead Academic Participating Site (LAPS). Wilmot’s longstanding activity as U10-funded members and growth in leadership and accrual as a LAPS site since 2018 indicate our continued investment in and commitment to clinical and translational research in cancer, particularly the development of and accrual to late-phase cancer clinical trials. In an era of increasing complexity in cancer biology and therapeutic development, our translational scientific program and dedication to the NCTN is critical for ultimate success. Wilmot’s Clinical Trials Program consists of a leadership group of faculty across the departments of medicine (hematology and medical oncology), radiation oncology and surgery who are highly invested in the NCTN. The increased leadership roles of NCI committees and cooperative disease groups, scientific achievements, ongoing mentorship and publication record position us well for continued impactful contributions to the NCTN mission. This ensures the growing number of Wilmot led NCTN trials, spanning the disease groups and academic departments, will continue. Between 2019 and 2024, Wilmot was able to activate NCTN clinical trials efficiently, accrue 157 patients annually on average and submit high quality data and specimens in a timely manner. With successful funding of this award, we plan to further increase these efforts across the network given our expanded regional presence, while continuing to focus on adolescent, young adult and geriatric populations. Wilmot has been a NCTN leader in accrual to pivotal studies, including those conducted on rare diseases, defining new standards of care. Wilmot and the University of Rochester are dedicated to the mission of the NCTN and will continue to contribute to the development and conduct of cooperative group trials at the highest level.