University Of Rochester

NIH Research Projects · FY 2026 · 2019-02

PROJECT SUMMARY The foveola, the 1-deg retinal region where cones are most densely packed, is of paramount importance for vision. Damage to this tiny portion of the retina has devastating consequences for many daily activities as humans use it to resolve fine details in the visual scene. Yet, primarily as a consequence of technical challenges, little is known about the mechanisms of foveal vision. A major difficulty in studying foveal functions comes from the need to finely control retinal stimulation. At this scale, both placing and maintaining a stimulus at a desired eccentricity is difficult, because of uncertainty in localizing the center of gaze, and because of the continual retinal motion caused by fixational eye movements, the slow eye drifts and small saccades (microsccades) that humans continually perform. Recent technical developments offer complementary strengths for overcoming these challenges: high- resolution retinal imaging allows for high-precision eye-tracking and gaze-contingent retinal stimulation while at the same time imaging the central fovea, yet it poses limitations in how psychophysical testing is conducted and makes it challenging to run high volume of subjects/trials. On the other hand, high-precision video eye-tracking coupled with gaze-contingent display control provides a flexible way for testing vision at the fine grain of the foveola and acquire large volume of data, but it does not provide information on foveal anatomy. To overcome these limitations this research uses a unique blend of these cutting-edge techniques for flexibly mapping visual functions and attention at the fine scale and linking oculomotor behavior, visual perception and anatomy in the foveola. The overarching goal of this research is to determine the limits and constraints of foveal vision and the mechanisms the visuomotor system relies on to compensate for these limitations, and to optimize fine spatial vision. Foveal vision will be investigated from three different perspectives: how eye movements and retinal anatomy jointly shape fine spatial vision in the foveola (Aim 1), how oculomotor plasticity and attention contribute to fine spatial vision in the foveola (Aim 2), how attention and the interplay with peripheral vision constrain the temporal dynamics of foveal processing (Aim 3). By bridging anatomy, oculomotor behavior and visual acuity, the research in Aim 1 will examine the fine modulations of visual acuity and cone density across the central fovea, how ocular drift varies in relation to cone density and whether the location chosen as the preferred retinal locus has an impact on acuity. Research in Aim 2 will examine the plasticity of microsaccades and how fine control of attention acts at spatial frequencies near the resolution limit and to compensate for anisotropies in sensitivity in the central fovea. Research in Aim 3 will elucidate how the temporal dynamics of vision and attention change foveally and extrafoveally and how sensitivity to co-occurring foveal and extrafoveal stimuli is modulated during fixation. The outcomes of this research may raise the possibility that fine control of attention and fixational eye movements can counteract vision loss within the central fovea in the early stages of certain diseases, and they may open the way for visual rehabilitation procedures acting on the fine control of eye movements and attention.

NIH Research Projects · FY 2025 · 2018-09

OVERALL CORE Every year, millions of children in the United States suffer child abuse and neglect (USDHHS, 2022). Our CAPSTONE Center for Multidisciplinary Research in Child Abuse and Neglect (P50) Project renewal goals are to advance a national resource center for conducting innovative research, disseminating emerging discoveries, and training investigators, clinicians, policy makers, and other professionals committed to preventing the occurrence of, and understanding the sequelae of, child maltreatment. The TRANSFORM renewal (Translational Research that Adapts New Science FOR Maltreatment Prevention) will continue to build on current state-of-the-art research methodologies and clinical practices to foster the next generation of professionals committed to addressing the deleterious and persistent personal and societal burden associated with child abuse and neglect. TRANSFORM builds upon the strengths of Mt. Hope Family Center, University of Rochester, including large longitudinal databases on child maltreatment. Additionally, a Resource Core incorporating statistical and methodological expertise will further strengthen TRANSFORM, extend our geographical reach, and expand our partnerships. TRANSFORM will continue to influence the field by serving as a national flagship Center on the etiology and sequelae of child abuse and neglect. We are grounded in the developmental psychopathology framework and adhere to a life course perspective in our research. TRANSFORM emphasizes a transdisciplinary approach, integrates contextual and cultural considerations as well as multigenerational influences to advance science and inform practice and policy. In doing so, TRANSFORM will apply the most advanced concepts and methods derived from child maltreatment research and leverage numerous longstanding relationships within the child welfare community to make its impact. To achieve its objectives, TRANSFORM will utilize two Research Projects, a pilot study, and three mutually-informative and integrated Cores: a Dissemination and Outreach Core, a Resource Core, and an Administrative Core. This ‘team science’ model brings together professionals with different backgrounds including: basic and applied scientists who provide much of the theoretical grounding for project hypotheses, program developers who are the architects of evidence-based programs, research methodologists who advise on the appropriate experimental designs for testing the models, measurements for assessing key constructs, and analytical methods for evaluating results, and child-serving professionals who will participate in dissemination activities. TRANSFORM will be led by Drs. Sheree Toth and Jennie Noll, internationally-recognized leaders in the field of child maltreatment, whose work spans over four decades and provides a solid foundation for continuing to conduct groundbreaking longitudinal, intergenerational, and intervention research that will contribute to widespread engagement across multiple child-serving systems.

NIH Research Projects · FY 2025 · 2018-08

This proposal seeks funding to continue support (R13 conference grant from NIAMS) for the Young Investigator Initiative (YII). The YII originated as one of the flagship programs of the United States Bone and Joint Initiative and was established to train the next generation of musculoskeletal investigators in the art of preparing high quality grant proposals. In the past year the YII has become a key program within the Orthopaedic Research Society (ORS). This change represents a new and exciting future for the YII as it expands the scope of young investigators that can benefit from the program and ensures a base of operation that will remain stable into the future. The permission letter for submission of this proposal is included in the appendix. The program/conference occurs over two weekends separated by 12-18 months. In the first phase of the YII, early stage clinical and basic science investigators learn the principles of proposing hypothesis-driven research and preparing significant and innovative grant proposals. They are assigned 2-4 experienced mentors who work with them in developing their research question. The young investigators then write and submit a grant proposal. After receiving a critique of their proposal from the awarding agency’s review group, they return for the second phase of the YII program (usually after 12-18 months). In this phase, the participants learn how to respond to the critique and refine and improve the application. The application is then resubmitted. This iterative process continues until the investigator receives funding. The success of the YII mentoring program has been remarkable. Since its establishment in 2005, over 1,000 scientists have applied for training. 550 have been accepted. These individuals have received 1,918 grants totaling over $600 million dollars. The success rate for funding is 59.9%. The scientists that comprise the mentoring faculty are all former NIH study section members with many years of experience. Their involvement in this program is voluntary. They participate because of their commitment to keep full the pipeline of new musculoskeletal investigators. The team responsible for managing the YII program is Nancy Lane, M.D., UC Davis, Howard Hillstrom, Ph.D. Hospital for Special Surgery and Edward Puzas, Ph.D. University of Rochester.

NIH Research Projects · FY 2025 · 2018-07

The University of Rochester Medical Center and its neuroscience investigators have provided over four decades of leadership and meaningful contributions to experimental therapeutics for neurological disease. Since the inception of the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) in 2011, the University of Rochester site (UR-NEXT) has contributed to its success by participating in 9 of 11 funded studies, by showing improved performance over the two prior award periods, and by sharing our expertise throughout the Network. The UR-NEXT site is uniquely positioned to contribute to rare disease research and the implementation of gene and gene-targeted therapy trials, and to train early-stage investigators to be leaders in the field. We have 51 potential co-investigators, including 25 experts in rare disease research or gene-therapy clinical trials, and 17 who are mentors within our NINDS T32 post-doctoral training program, Experimental Therapeutics of Neurological Disease, now in its 32nd year of continuous funding. Many of these investigators lead rare disease clinical trial readiness and enabling research programs with regional, national, and international reach. UR-NEXT will continue to improve its performance as an exemplary clinical trial site that conducts efficient, equitable, and high-integrity NeuroNEXT clinical trials for adult and child neurological diseases, and bolster our qualifications and achievement by: 1) expanding our cadre of exceptional co-investigators with special expertise in experimental therapeutics and to foster their successful contributions to NeuroNEXT and the Gene Therapy Consortium; 2) leading a comprehensive effort of community and multistakeholder engagement, including building authentic relationships with trusted community members, to customize and improve our approach to recruitment and retention, and the diversity in our clinical trials; 3) strengthening our approach to performance improvement by deploying “Study Start-Up Bundles”, a Community-Informed Recruitment and Retention Activity Questionnaire, and by performing a post-study Recruitment Strategy Analysis for each NeuroNEXT clinical trial; 4) integrating early-stage investigators into the career development and training opportunities within our experimental therapeutics training program to ensure their successful transition to an NIH/NINDS-sponsored career development award; and 5) providing leadership in rare disease research, gene therapy trials, and the incorporation of digital tools while collaborating and disseminating our successes across NeuroNEXT, NINDS, and beyond. UR-NEXT will be inclusive, rigorous researchers, team players, boundary crossers, process innovators, skilled communicators, and system thinkers to equitably improve the translational process and the lives of children, adults, and families affected by neurological disease.

NIH Research Projects · FY 2025 · 2018-05

Project summary The immune response to Toxoplasma gondii, a prevalent foodborne pathogen, relies heavily on the cytokine IFN-γ. Previous research has primarily focused on the role of dendritic cells and macrophages in triggering IFN- γ responses. However, the contribution of non-myeloid cells, particularly intestinal epithelial cells (IECs), in IFN- γ-mediated host defense remains poorly understood. Our preliminary data suggest that IECs play a central role in inducing intestinal immunopathology during T. gondii infection, characterized by tissue damage without a significant increase in parasite burden. We have also identified a novel mTOR-dependent mechanism of Paneth cell death, a subset of IECs, in IFN-γ-induced immunopathological responses. However, the responses of other IECs to IFN-γ are largely unknown. In this competitive renewal, our goal is to gain a mechanistic understanding of IEC-specific IFN-γ-mediated immunity to T. gondii by investigating both protective and immunopathological responses. We have two specific aims: Aim 1: Determine intestinal epithelial cell-specific responses to IFN-γ during T. gondii infection. In this aim, we aim to identify the specific IECs that mediate IFN-γ-dependent immunopathology triggered by T. gondii infection and define the lineage-specific responses of IECs to IFN-γ during mucosal infection. Aim 2: Identify the IFN-γ-induced metabolic adaptations of epithelial cells contributing to the pathological response during T. gondii infection. Building upon our previous findings of mTOR inactivation and Paneth cell death, we will investigate the metabolic changes in IECs triggered by IFN-γ. By the completion of this aim, we will have a comprehensive understanding of the cellular and molecular mechanisms underlying IFN-γ-mediated intestinal pathology during T. gondii infection. The proposed project is significant and innovative due to its novel concept of IFN-mediated immunity and immunopathology at the site of infection, and the experimental tools developed to accomplish the goal of this proposal during the previous funding period.

NIH Research Projects · FY 2026 · 2018-04

PROJECT SUMMARY The principal investigator (PI), Dr. Supriya Mohile, of this K24 renewal proposal leads an independently funded patient-oriented geriatric oncology research program at the University of Rochester Wilmot Cancer Institute. Over the last K24 funding period, Dr. Mohile completed two large multi-site cluster-randomized trials that evaluated whether geriatric assessment and management (GAM) improves outcomes of older patients with advanced cancer. GAM, a validated patient-centered approach for assessing health status, identifies older patients with cancer who are at risk of adverse outcomes and guides management for cancer treatment and for aging-related conditions. Both trials demonstrated, for the first time, that a GAM intervention improves patient- centered outcomes (communication and patient/caregiver satisfaction) and clinical outcomes (treatment toxicity, falls, and polypharmacy). Integrally involved in this research, mentees at the University of Rochester and through the Cancer and Aging Research Group (CARG) have utilized data from the GAM trials to successfully compete for their own career development and independent awards. Dr. Mohile currently mentors ten early career scientists. Mentees have received over 20 grants and have published over 80 manuscripts with Dr. Mohile. Dr. Mohile is currently a primary mentor or co-mentor on seven career development awards. Further, over the last K24 funding period, Dr. Mohile successfully competed for three new R-level awards as PI from the Patient Centered Outcomes Research and the National Institutes of Health to evaluate strategies for implementing GAM in oncology practices and to expand understanding about cancer treatment tolerability in older adults. The original K24 allowed Dr. Mohile and her mentees to enhance skills in communication research; the renewal will allow them to learn about implementation science and leadership with expert consultants at the University of Rochester and in CARG. The overarching aims of this proposal are: 1) to develop and evaluate implementation strategies for GAM in oncology practices; and 2) to examine treatment tolerability in older patients with advanced cancer and aging-related conditions starting a new high-risk cancer treatment regimen. This research will have a positive impact by providing information on pragmatic mechanisms for implementing GAM in oncology care. Importantly, this proposal will allow for the career development of mentees pursuing patient-oriented research focused on geriatric oncology, an understudied field. Through funded research, an endowment from the Wilmot Cancer Institute, and the NIA-funded CARG (MPI: Mohile), Dr. Mohile has the resources to continue to foster the careers of investigators interested in geriatric oncology research across the academic career trajectory. The renewal of this K24 Award will enable Dr. Mohile to expand mentoring to enhance the growth of patient-oriented research in geriatric oncology.

NIH Research Projects · FY 2026 · 2018-03

PROJECT SUMMARY Seeing a speaker’s face can greatly improve one’s ability to understand what they are saying, especially under adverse hearing conditions. This phenomenon has been attributed to the multisensory integration of audio and visual speech. Decades of research suggests that such integrative mechanisms come in two forms based on “when” the audio and visual speech are integrated: 1) early integration at the acoustic level, before speech acoustics have been transformed into linguistic representations; and 2) late integration at the linguistic level, where the visual system supplies its own linguistic representations that constrain the inferences being made about audio speech. This has led some to propose that audiovisual speech integration is a multistage process. However, the multistage models that have been proposed lack detail on how speech acoustics and visible articulations are initially transformed into linguistic representations. And, more generally, they have been vague on how visual speech constrains linguistic categorization. Progress on updating these models has been slow over the past decade, in large part because the field has overly relied on – admittedly interesting and important – paradigms involving discrete (often illusory) speech stimuli. To fully characterize early integrative processes – likely based on the correlated dynamics of visual and auditory speech – and later integrative processes – likely based on how the form of visual articulators helps with linguistic categorization – surely requires the use of ongoing, natural audiovisual speech. In this project, we propose an updated model of multistage audiovisual speech processing. This model is built on the hypothesis that hierarchical speech processing occurs in both the auditory and visual systems – and that different hierarchical speech representations in the visual system flexibly influence different hierarchical levels of processing in the auditory system, depending on the quality of the acoustic input and the task. We aim to test several predictions generated by this model. A first prediction is that correlated motion from visual speech enhances auditory selective attention and, thus, auditory cortical sensitivity to acoustic speech, while visual articulatory cues enhance the categorization of auditory speech into linguistic units. A second prediction is that visual speech aids in speech recognition according to an information theoretic process at the sub-lexical (i.e., phoneme-by-phoneme) level. Finally, we predict that different visual speech representations differentially influence audio speech processing as a function of acoustic experience/quality. We will test this by characterizing such processing in people who vary in their level of acoustic speech experience, namely deaf individuals who do and do not use cochlear implants, as well as typically hearing individuals. Ultimately, this project will provide a rigorous test of an updated model of natural audiovisual speech processing in the human brain. We also expect it to produce methods, paradigms and measures that will be valuable in future basic and clinical research. And we have assembled a team that is ideally suited to deliver on these goals.

NIH Research Projects · FY 2025 · 2017-09

ABSTRACT The retinal pigment epithelium-choriocapillaris (RPE-CC) complex is the primary site of disease pathogenesis in several eye diseases, including age-related macular degeneration (AMD) and related macular dystrophies, like Sorsby’s fundus dystrophy (SFD). Notably, sub-RPE accumulation of tissue inhibitor of metalloproteinase 3 (TIMP3) is a prominent feature of SFD/AMD. However, it is not known “how” sub-RPE TIMP3 accumulation promotes SFD/AMD pathology. This is partially because the RPE-CC is a functional composite making it difficult to study the contribution of spatial changes in RPE versus CC layer during disease development in vivo. Furthermore, the lack of a representative model of the RPE-CC in vitro has significantly impacted our ability to study RPE-CC interaction in vitro. Using induced pluripotent stem cells (iPSCs), we have developed an iPSC- RPE-CC model that recapitulate key features of both healthy and AMD/SFD eyes. Specifically, iPSC-RPE-CC shows evidence of fenestrated CC-like vasculature and Bruch’s membrane like ECM. Similarly, SFD iPSC-RPE- CC displays two central hallmarks of SFD/AMD, drusen and choroidal neovascularization (CNV)-like pathology. Notably, longitudinal analyses of control versus SFD iPSC-model showed that sub-RPE TIMP3 accumulation occurs relatively early and precedes maculopathy cellular events. Furthermore, our preliminary proof of concept studies shows that sub-RPE TIMP3 accumulation in the SFD iPSC model promotes pro-maculopathy cellular changes via dysregulated lipid metabolism and sterile inflammation. Based on these strong preliminary studies, the overall goal of this proposal is to establish the independent contribution of sub-RPE TIMP3 accumulation to AMD/SFD pathology development. We will perform spatial (RPE versus CC) and temporal (e.g., prior and after drusen formation) manipulation of TIMP3 expression/activity in i) SFD iPSC-RPE-CC and ii) control iPSC-RPE- CC cultures (iPSCs derived from healthy subjects with normal vision) to test the hypotheses that sub-RPE TIMP3 accumulation leads to dysregulated lipid metabolism and sterile inflammation and consequently i) drusen beneath the RPE monolayer and ii) CC atrophy and CNV. From a therapeutic standpoint, we will pharmacologically target dysregulated lipid metabolism and sterile inflammation in SFD/AMD iPSC models.

NIH Research Projects · FY 2025 · 2017-09

Abstract: Immune cell response to ocular inflammation is involved in various prevalent retinal diseases that lead to blindness such as glaucoma, age related macular degeneration, uveitis and diabetic retinopathy. However, the microscopic and translucent nature of circulating and resident immune cells has made study of such cells challenging in the living eye. Further complicating matters, immune cells move at fast speeds (centimeters/second) when circulating in big vessels and glacial pace at micrometers/minute when in tissue. This project will combine a number of innovations that overcome many of these challenges to study single immune cells in the living eye in their response to inflammation. The use of adaptive optics scanning light ophthalmoscope (AOSLO) to image mouse retina will provide a noninvasive in vivo imaging method that can resolve single immune cells and track their behavior through the entire course of inflammation. With our AOSLO, we have recently demonstrated that phase contrast combined with both fast and time-lapse videography now enables us to visualize these microscopic immune cells using near infrared light alone and without fluorescence contrast. Therefore, this project will seek to study immune cell dynamics in two models of inflammation in the living mouse eye and track the cellular responses to initiation, escalation and resolution. And while the approach is non-invasive and does not require use of fluorescence, we will combine fluorescence confirmation of specific leukocyte populations that contribute to the inflammatory response. Our project tackles three synergistic aims to track the dynamic nature of inflammation using two established models: Model 1) An endotoxin induced uveitis model using lipopolysaccharide (LPS) injection in vitreous of the eye. This results in an acute, short-term form of inflammation. We will track the initial escalation of inflammation in the retina by monitoring behavior of tissue resident microglia and systemic early responder neutrophils. And Model 2) An autoimmune uveitis condition that is induced in a healthy host mouse by injecting a subpopulation of fluorescent CD4+ T cells that are reactive to interphotoreceptor retinoid binding protein from a different donor mouse. Here, we will characterize the behavior of these foreign reactive T cells in healthy retina, and their interaction with the host immune system. In both inflammatory models, we will characterize the initiation, escalation, infiltration and resolution of immune cells in the retina by longitudinally tracking their behavior from hours to days to months. Finally, in a third aim, we will also study the changes in blood flow in response to these inflammatory models. For both endotoxin mediated and autoimmune inflammatory models described above, we will monitor structural and functional changes in retinal vasculature from the largest arteries and veins to single file flow capillaries to understand the interplay between blood flow and immune cell arrival into the retina. Already, we have observed that the vascular response is not homogeneous, and arterioles, venules and capillaries respond in different ways to the inflammatory insult and likely mediate the location, arrival and type of immune cell passage. Together, the longitudinal monitoring of inflammation and blood flow will provide new insights to the retinal immune response using innovations in high-resolution ophthalmoscopy.

NIH Research Projects · FY 2025 · 2017-09

Abstract Bone infection caused by Staphylococcus aureus remains the bane of orthopaedic surgery, as diagnostics, prophylactics and treatments have significant shortcomings that result in catastrophic outcomes for patients, and crippling healthcare costs. Although the incidence of infection following primary total joint replacement (TJR) is low (~1%), reinfection rates are very high (15-40%), which has led to the orthopaedic paradigm that S. aureus infection of bone is incurable. Additionally, prosthetic joint infection (PJI) is known to be a non-random event that is largely determined by patient-specific factors. To address this, we proposed the original Center of Research Translation on the Osteoimmunology of Bone Infection (CoRTOBI) to test the hypotheses that: 1) there must be a reservoir of S. aureus that is not affected by standard of care treatments, and 2) the patient’s immune proteome against S. aureus antigens impacts the incidence and outcome of bone infection. Our work on this has resulted in innovative technologies that are being translated to the clinic by industry partners, and several seminal discoveries that we will continue to work on in this renewal, including: 1) S. aureus colonization of the osteocyte lacuno-canalicular network (OLCN) of live bone, 2) novel small molecule inhibitors that specifically target these mechanisms that can be 3D-printed into custom spacers as adjuvants to antibiotics, 3) development of a custom multiplex immunoassays to elucidate the immune proteome of S. aureus, 4) development of in vivo imaging to quantify “the race for the surface” of implants in real time, and 5) identification of anti-IsdB responses as susceptible immunity vs. anti-Gmd responses as protective immunity in mice and patients with culture confirmed S. aureus bone infection. Based on this success, we propose continuation of CoRTOBI with its Administrative Core that provides operational and fiscal management of the CoRTOBI, as well as a Biostatistics Sub-Core, an Enrichment Program, and a Pilot and Feasibility Project Program. We will also continue the Research Projects. Project 1 is focused on elucidating the mechanisms of S. aureus invasion of the OLCN, and developing novel antibiotic and adjuvant impregnated 3D-printed spacers. Project 2 is focused on elucidating the mechanism responsible for the susceptible immune proteome in patients, translating our discovery of five protective antigens with a novel multivalent mRNA vaccine, and bioinformatic assessment of patient-specific factors with the strain of S. aureus with which they are infected. The Projects will be supported by an Osteoimmunology Research Core, which will provide state of the art imaging, microfabrication and immunoassay analyses. The Core will also further innovate these technologies into novel outcome measures and enhance their clinical utility towards commercial products. At the conclusion of this CoRTOBI we will have in-depth knowledge of S. aureus OLCN invasion and immune evasion, as well as novel candidate clinical assays, antimicrobials and vaccines, to diagnose, prevent and treat the most serious bone infections, whose outcomes have not improved over the last half century.

NIH Research Projects · FY 2026 · 2017-07

Project Summary/Abstract People with fetal alcohol spectrum disorders (FASD) experience barriers to care and a lower quality of life (QOL). Responsive to the Collaborative Initiative on FASD (CIFASD5) objectives of improving interventions and early case identification, this proposal evaluates three developmentally-appropriate and scalable interventions to improve QOL across the lifespan. Each intervention leverages technology to increase accessibility and overcome significant barriers to care. These technological interventions are versatile with good potential for dissemination, offering high potential public health impact. All three interventions are theoretically grounded in self-determination theory (SDT) and are integrated with useful best practices in “FASD-Informed Care,” derived from FASD research, clinical wisdom, and policy. Our methodological approach builds on our success developing mobile health (mHealth) applications within CIFASD4, which has included the Families Moving Forward (FMF) Connect app for caregivers of children ages 3-12 (U01 AA026104) and the My Health Coach app for adults with FASD (UH2 AA02050). Study aims will be accomplished using our established systematic user-centered design approach to mHealth interventions, which emphasizes engagement of key stakeholders throughout the development and testing process. Trial design and outcome measurement are guided by implementation science frameworks with the vision towards optimizing success of future dissemination in community settings. Aim 1 tests whether the “Provider-Assisted FMF Connect” intervention and an Extension of Community Healthcare Outcomes (ECHO) implementation package increases mental health providers’ (n=250) FASD-informed care knowledge, self- efficacy, and practice change (including screening and diagnosis of FASD). We hypothesize mental health providers trained in Provider-Assisted FMF Connect through ECHO tele-mentoring will evidence greater practice change compared to providers in self-directed implementation or waitlist conditions. A larger-scale efficacy trial, Aim 2 will test whether the My Health Coach app improves SDT and QOL outcomes for adults with FASD (n=120). Patterns of app usage relating to outcomes will guide further app refinements and dissemination. Leveraging advisory board and focus group input, Aim 3 will develop and assess usability of a caregiver-assisted mHealth app for adolescents called the “Determined” app system. The Determined app system will include both adolescent and caregiver apps, with synchronized features supporting adolescent self-determination skill building, caregiver autonomy-supportive parenting, and family QOL. Inclusion of these three aims across the lifespan facilitates efficient and mutually informative intervention development. It also addresses gaps in intervention research, especially in adolescence and adulthood. All three aims draw from diverse geographic regions, benefitting directly from recruitment via other CIFASD sites yet expanding beyond them. To other CIFASD5 projects and investigators, we provide much needed, scalable interventions to offer their participants and a clinical setting to test new diagnostic innovations. From findings of our CIFASD colleagues, we will glean content vital to improve our interventions.

NIH Research Projects · FY 2025 · 2017-07

The major goal of the project is to elucidate the molecular mechanisms underlying cardiac microvascular fatty acid transport dysfunctions and its involvement in heart failure with preserved ejection fraction (HFpEF) under diabetic conditions. Diabetes mellitus, one of the major leading chronic morbidities worldwide, is continually increasing with a high prevalence in the United States and throughout the world. Cardiovascular complications are mainly responsible for the high morbidity and mortality in people with diabetes. Type 2 diabetes (T2D) is one of key risk factors for the development of HFpEF, and the prevalence of HFpEF is rising in parallel with global surging of T2D. However, the molecular mechanisms linking diabetes to HFpEF are poorly understood, and currently there are no effective treatments available for HFpEF. Endothelium, a cell layer lining of blood vessels, is an independent organ that functions as a barrier for the nutrient shuttling. The neglected role of endothelium in controlling the metabolic homeostasis is beginning to evolve. However, the role of coronary microvascular endothelial fatty acid shuttling in diabetic heart and the underlying molecular mechanisms remain elusive. Sirtuin 6 (SIRT6), a well-recognized longevity gene, regulates genome stabilization, DNA repair, inflammation and metabolic homoeostasis. SIRT6 is a histone deacetylase that targets the acetylation of histone 3 lysine 9, an epigenetic marker for active gene transcription. Recent studies indicate that SIRT6 deficiency is associated with metabolic disease, and SIRT6 has been proposed as a potential therapeutic candidate fighting the metabolic syndrome epidemic. In parallel, emerging evidence from our group suggests that SIRT6 plays a crucial role in regulation of cardiac endothelial homeostasis. Specifically, we have recently found that SIRT6 modulates coronary microvascular endothelial fatty acid transport and cardiac lipid metabolism under the nondiabetic and diabetic conditions, which is implicated in the pathogenesis of T2D-induced HFpEF. As such we propose that an alternation of SIRT6 expression and function in coronary microvascular endothelial cells under diabetic conditions could cause cardiac microvascular endothelial fatty acid transport abnormality and cardiac metabolic disarrangement, which may cause diabetes-associated diastolic dysfunction. We will use the combination of in vitro and in vivo experiments to test this novel hypothesis. Results from proposed studies would help to understand molecular basis of endothelial FA transport, and facilitate the development of new therapeutic approaches, such as enhancing SIRT6 expression and activity, to limit diabetes-associated HFpEF, a deadly disease without any effective therapy.

NIH Research Projects · FY 2025 · 2017-02

In adulthood, stroke damage to the primary visual cortex (V1) causes a large, contralateral loss of conscious vision referred to as hemianopia or cortical blindness (CB). Although this condition affects up to ½ million new cases each year in the US alone, there is a total lack of accepted vision restoration therapies – in marked contrast with early-onset physical therapies prescribed to those with motor cortex damage. Two decades of work in chronic CB patients, whose deficits are deemed stable, permanent and thus amenable to scientific study, have generated one method consistently able to recover vision after long-standing V1 damage: gaze- contingent visual training to detect or discriminate stimuli in the blind field. Over the last 2 grant periods, we have taken clear leadership in the field, providing hope that an effective therapy for CB may finally be on the horizon. However, while characterizing training-induced recovery and its underlying mechanisms, we also found that recovery in chronic CB requires months of daily training and the vision restored is low-contrast, coarse, impaired by excessive internal processing noise and restricted to the blind field perimeter. Accumulating evidence suggests that these limitations may occur because chronic patients have lost a substantial portion of neurons that contribute to vision fundamentals not only in V1, but through retrograde degeneration, in the dorsal lateral geniculate nucleus (dLGN) and retina. Our new pilot data show subacute CB patients <6 months post-stroke to lack significant signs of degeneration, and more than half of subacutes tested retained visual discrimination abilities in their blind field, which disappeared by the start of the chronic period (6 months post-stroke). Moreover, when training was administered to subacutes, they recovered the same discrimination abilities as chronics, but much faster, and with recovery extending deeper into their blind field. These data form a strong premise for testing the hypothesis that substantial differences in plastic potential between subacute and chronic V1-stroke visual systems can be exploited to maximize visual restoration in CB, and that the extent of recovery attainable is limited by the amount of retrograde degeneration sustained. We now propose to: (Aim 1) assess how visual performance relates to structural evidence of retrograde degeneration in the subacute period post-V1-stroke. We will then (Aim 2) assess the impact of subacute training on blind-field functions, the progression of retrograde degeneration and the continued potential for training-induced recovery in the chronic period. Finally, we will (Aim 3) contrast mechanistic substrates of perceptual learning in subacute & chronic CB. All in all, the work proposed is unique in the field, which it stands to advance significantly by generating entirely new knowledge and understanding of the change in visual plastic potential with time in the early period after permanent V1 damage in humans. This knowledge is important both neuro-scientifically, and for devising more effective treatment and realistic outcome expectations for this growing patient population.

NIH Research Projects · FY 2024 · 2016-09

Abstract The NIH Environmental influences on Child Health outcomes (ECHO) Program seeks to understand the impact of early environmental influences on child health and development – with a special emphasis on Pre-, Peri-, and Postnatal Health, Upper and Lower Airways, Neurodevelopment, Obesity, and Positive Health – and to enhance these areas of health and development. The Rochester-Magee award in the first phase of ECHO (UG3/UH3 OD023349) was a pregnancy cohort that followed children through age 4 years. In this proposal, which is responsive to RFA-OD-22-018 for the second phase of ECHO, we will recruit an additional pregnancy cohort of 375 pregnancies (across the first 5 years) and conduct a pediatric follow-up of our existing ECHO cohort (12601) and two Rochester-based ECHO cohorts that were part of other multi-site awards in first phase of ECHO: PROP/PRISM and TIDES-Rochester. Including these two additional cohorts in our pediatric follow- up plans increases the number of ECHO cohorts that are carried forward from the first to the second phase of ECHO and creates economies of scale and efficiencies for our pediatric follow-up. Collectively, we aim to follow 375 children across the three consolidated Rochester-based ECHO cohorts. In response to the RFA, we propose two areas of specialized outcomes, Neurodevelopment & Upper and Lower Airways/Asthma, and two areas of specialized exposures, Chemical exposure & Prenatal Immune Activation/Inflammation, that reflect expertise of the research team and measurement concentration and in- depth data related to the pregnancy and pediatric cohorts. Throughout the UG3 and UH3 phases of the second phase of the ECHO program we will institute practices to maximize retention of existing participants, ensure recruitment of diverse new pregnant/preconception participants, and implement the established ECHO Cohort Protocol with high fidelity. We will also lead novel and solution-oriented research that capitalizes on the data already on the ECHO platform and research that takes advantage of our specialized areas of expertise to understand how pre-conception, perinatal, and early postnatal exposures shape child health outcomes.

NIH Research Projects · FY 2025 · 2016-09

Abstract The NIH Environmental influences on Child Health outcomes (ECHO) Program seeks to understand the impact of early environmental influences on child health and development – with a special emphasis on Pre-, Peri-, and Postnatal Health, Upper and Lower Airways, Neurodevelopment, Obesity, and Positive Health – and to enhance these areas of health and development. The Rochester-Magee award in the first phase of ECHO (UG3/UH3 OD023349) was a pregnancy cohort that followed children through age 4 years. In this proposal, which is responsive to RFA-OD-22-018 for the second phase of ECHO, we will recruit an additional pregnancy cohort of 375 pregnancies (across the first 5 years) and conduct a pediatric follow-up of our existing ECHO cohort (12601) and two Rochester-based ECHO cohorts that were part of other multi-site awards in first phase of ECHO: PROP/PRISM and TIDES-Rochester. Including these two additional cohorts in our pediatric follow- up plans increases the number of ECHO cohorts that are carried forward from the first to the second phase of ECHO and creates economies of scale and efficiencies for our pediatric follow-up. Collectively, we aim to follow 375 children across the three consolidated Rochester-based ECHO cohorts. In response to the RFA, we propose two areas of specialized outcomes, Neurodevelopment & Upper and Lower Airways/Asthma, and two areas of specialized exposures, Chemical exposure & Prenatal Immune Activation/Inflammation, that reflect expertise of the research team and measurement concentration and in- depth data related to the pregnancy and pediatric cohorts. Throughout the UG3 and UH3 phases of the second phase of the ECHO program we will institute practices to maximize retention of existing participants, ensure recruitment of diverse new pregnant/preconception participants, and implement the established ECHO Cohort Protocol with high fidelity. We will also lead novel and solution-oriented research that capitalizes on the data already on the ECHO platform and research that takes advantage of our specialized areas of expertise to understand how pre-conception, perinatal, and early postnatal exposures shape child health outcomes.

NIH Research Projects · FY 2025 · 2016-09

Project Summary/Abstract: Parkinson's disease (PD), Lewy Body Dementia (LBD) and related disorders are the second most common neurodegenerative illness affecting over 1.5 million Americans and are the 14th leading cause of death in the United States. Notably, while PD is traditionally described by motor symptoms (e.g. tremor), more recent research demonstrates that nonmotor symptoms such as pain, depression, and dementia are leading causes of mortality, quality of life (QOL), nursing home placement and caregiver distress. Regarding models of care for PD and LBD, evidence suggests that care including a neurologist results in lower mortality and nursing home placement than care solely from a primary care physician. Unfortunately, there is also significant evidence that many of the needs most important to patients and family (e.g. pain, planning for the future) are poorly addressed under current care models. Palliative care is an approach to caring for individuals with serious illness that addresses multiple causes of suffering including medical symptoms, psychosocial issues and spiritual needs. While developed for cancer patients, palliative care approaches have been successfully applied in other chronic progressive illnesses. There is expanding interest in applying these principles to PD and LBD. A small but growing cadre of centers now offer outpatient palliative care for PD and LBD with mounting evidence of efficacy including a randomized trial of academic-based outpatient palliative care led by the PI. While this work is critical to forwarding this field, further work is needed to provide models that can be widely disseminated in the community where the majority of patients receive their care. The current proposal addresses this gap and builds on lessons learned our original R01 grant by assessing the effectiveness and feasibility of a novel community-based intervention that builds online learning communities around palliative care for community neurology practices and augments care for patients and family around social support communities. We hypothesize this intervention will improve patient QOL, caregiver burden and community provider career satisfaction. Our Specific Aims are to: 1) Determine the a) effectiveness and b) feasibility of a novel community- based outpatient palliative care model for PD and LBD; 2) Describe the effects of this model on patient and caregiver costs and healthcare utilization; and 3) Identify opportunities to optimize this model by: a) describing patient and caregiver characteristics associated with intervention benefits; and b) through direct patient, caregiver and provider interviews. Innovations of our approach include the use of online learning communities to implement primary palliative care with neurologists and the use of online networks to provide team-based support and peer connections to patients and families. The research is significant because it tests a potentially more efficient and effective model of providing palliative care to persons affected by PD and LBD, and, in conjunction with other work conducted by our group, will provide data relevant to patients, healthcare providers, policy makers and other stakeholders to guide future dissemination efforts in this field.

NIH Research Projects · FY 2024 · 2016-08

No abstract provided

NIH Research Projects · FY 2024 · 2016-08

CORE J. TL1 TRAINING PROGRAM – PROJECT SUMMARY/ABSTRACT The University of Rochester Clinical and Translational Research Institute (UR CTSI) TL1 NRSA Training Core aims to produce innovative, cross-trained, experienced researchers who contribute to the rapidly evolving and shifting needs of the US clinical and translational research workforce. Our long-term model of training graduate students, year-out medical students, and postdoctoral fellows across the translational science spectrum has adapted to shifting opportunities and discoveries in science, trends in educational strategies and skills, and serves the University's distinct multicultural, geographic, and multidisciplinary needs. We focus on immersion in mentored research training and experience at multiple levels of the training pipeline to engage communities not traditionally represented among researchers, and to provide formal degree credentials through innovative programming. Leveraging the strengths of our institution, we aim to promote exposure and opportunities in the focus areas of our parent CTSA award, in particular toward: 1) building a culture of data excellence supporting extensive data integration, and 2) extending our Learning Health System to improve population health by taking clinical and translational research beyond the walls of academia. We accomplish our goals by: 1) offering a comprehensive, wrap-around, multi-leveled learning/experiential environment, 2) offering the opportunity for completion of innovative credentials to promote a career in clinical and translational science, and 3) immersion in stage-appropriate, mentored clinical/ translational research that connects populations, data, and innovations. We expand on our previous innovative strategies and programs that have been successful in recruiting underrepresented populations into our clinical research training program, which is a hallmark of the TL1. Our specific aims are as follows: Aim 1: Contribute to a diverse, well-trained clinical research workforce by recruiting, mentoring, and immersing students into a focused set of training opportunities across the translational research spectrum. Aim 2: Create a heterogeneous Trainee pipeline and stimulate interest in clinical research training and career paths by engaging priority populations (1: Deaf Trainees; 2: Underrepresented Communities; and, 3: Undergraduate students) in short-term immersive research exposures. Aim 3: Engage alumni working in a variety of sectors and industries to promote exploration of translational training and careers within and outside of academia. Aim 4: Harmonize the TL1 Program with the Administrative Core's Evaluation Working Group to ensure continuous program improvement using multiple metrics to review, revise and improve training strategies and quality as well as best practices and mentor training and evaluation. The TL1 program closely aligns governance with the KL2 program and integrates with the Hub's Translational Workforce Development Function, aiming to create and enhance a contemporary, flexible, multi-skilled base of researchers and contributors to the clinical research enterprise with practical experience across disciplines and beyond the walls of academia.

NIH Research Projects · FY 2024 · 2016-08

Contact PD/PI: Zand, Martin S CORE O: OVERALL – PROJECT SUMMARY/ABSTRACT The Clinical and Translational Science Institute (UR CTSI) is the research engine of the University of Rochester Medical Center. The UR CTSI has catalyzed research throughout the University, building a robust translational research ecosystem. During the next five years, the UR CTSI will focus on “translational research without walls,” moving beyond the physical and virtual confines of institutions. We will accelerate integration of translational research with the Learning Health System. We will expand our innovative approaches to dissemination and implementation (D&I) research including: a new and dedicated D&I KL2 scholar position, a Health-Equity Focused Dissemination and Implementation Optional Function; and a collaborative pilot program focused specifically on D&I projects within the Learning Health System. We will develop and disseminate novel educational materials and methods. We will create a translational research data ecosystem that seamlessly integrates data across the translational spectrum by linking our research and clinical data warehouses. We will implement the ACT/SHRINE cohort discovery software and make extensive use of Center for Data to Health (CD2H) tools, ontologies and working groups. We will expand education efforts across our pilot programs to achieve translational research data and analytic excellence. We will enhance translational research collaborations at the local and national levels across the spectrum of stakeholders. We will continue our extensive participation with the CTSA Coordinating Centers. We will extend our successful program in community-based participatory research, facilitating multidisciplinary team formation with community members. We will expand our local and national collaborations. We will educate the next generation of translational science workforce leaders, expanding our approaches to ensure competence in the collaborative, technical, and regulatory skills necessary to accelerate the translation of high impact research to clinical applications. We will develop and disseminate novel educational materials, investigator support, and methods. We will catalyze the development, implementation and dissemination of methods and processes that advance translational research locally and nationally across the CTSA Consortium through methods to advance remote data and sample collection; speeding basic and early stage research with regulatory support and industry sponsorship; and programs for rapid trial evaluation, negotiation, and approval. We will enhance our Participant and Clinical Interactions Function to accommodate teleresearch visits and remote data and sample capture methods. We will employ our existing strengths to implement and manage multi-site research studies. Page 172 Project Summary/Abstract Contact PD/PI: Zand, Martin S CORE O. OVERALL –

NIH Research Projects · FY 2025 · 2016-08

External stressors have implications for the health and well-being of families and children, including increased domestic violence and harsh parenting. Despite evidence indicating that these may increase rates of interparental hostility and parent-child difficulties, little is known about the lasting effect on families, particularly how it may modulate the degree and nature of the interdependencies between family relationships or subsystems in ways that modify family functioning. Grounded in the theoretically rich conceptualizations of family systems and spillover processes, this application seeks to explore how the extra-familial perturbations modify associations between interparental hostility and discord and harsh, punitive parenting. This application builds on an existing dataset (Phase 1, N = 235 families) that was collected over a three-year period immediately and we propose to collect three additional waves of data to continue to chart longitudinal effects. The strength of this application involves the utilization of a quasi-experiment design for family functioning, and both phases (six waves in total) will utilize multi-method, multi-informant, and multi-level longitudinal design to assess ecological contexts, family dynamics, parent and child characteristics, and parenting behaviors. This study will elucidate how external stressors may influence spillover processes and may have enduring effects on family functioning and advance new process-oriented approaches through the mediating mechanism of parental neurobiological and cognitive self-regulation. Furthermore, the present application will identify the preexisting factors as risk or protective factors in the spillover processes. The results of this application will have significant implications for understanding family functioning and have high potential to generate knowledge on targets for evidence-based prevention programs.

NIH Research Projects · FY 2026 · 2016-08

Project summary Eukaryotic genomes contain arrays of tandemly repeated non-coding sequences that we currently know little about—satellite DNAs. Typically found near centromeres, telomeres, and on Y chromosomes, satellite DNAs can comprise over 50% of some eukaryotic genomes. They are known to change rapidly in sequence and genomic location, which can cause genetic incompatibilities between closely related species. The misregulation of satellite DNA can have serious consequences for genomic stability and cancer formation. Despite being a ubiquitous part of genomes and having important effects on cellular functions, the lack of genetic, genomic, and molecular tools to study tandemly repeated sequences has stymied progress towards understanding satellite DNA evolution and function. For example, satellite DNAs are particularly challenging to sequence, assemble, and manipulate. Recent developments in sequencing and genome editing technologies circumvent some of these problems. This proposal integrates genomic, molecular, and cytological methods to study the evolutionary and functional genomics of satellite DNA in Drosophila genomes. The PI has developed new genomic approaches and resources to study satellite DNA evolution with unprecedented resolution. The PI will use a comparative genomics approach to study changes in satellite DNA sequence, abundance and organization over evolutionary time and to determine the evolutionary forces driving these changes. This proposal also aims to develop comprehensive population genetic models of satellite DNA evolution that take into consideration different types of natural selection based on functional aspects of satellite DNAs studied in this proposal and leverage empirical data about satellite DNA organization generated by the PI. Little is currently known of satellite DNA function: the precise genetic manipulation of satellite DNAs with site-specific gene editing approaches had not been possible in the past due to a lack of unique target sites. The PI has used their assemblies of satellite loci to identify target sites and has successfully manipulated satellite DNA loci using CRISPR/Cas9-based genome editing techniques. They have made precise genomic deletions and duplications of satellite DNA in Drosophila melanogaster that they will use to test specific hypotheses about the regulation, fitness effects, and selfish genetic behavior of satellite DNA. This proposal will also leverage the new molecular genetic resources the PI created to manipulate satellite DNA expression to ask questions about their functions in chromosome segregation and chromatin organization. These experiments will have broad implications not only for genome evolution and speciation, but also for understanding the regulation of satellite DNA in cancer and aging.

NIH Research Projects · FY 2025 · 2016-08

Summary Within a cell, a number of pathways contribute to the repair and clearance of proteins and are required for maintaining protein homeostasis (proteostasis). A common feature of proteostatic pathways is their ability to act on a range of client proteins that vary based on cellular and environmental conditions. The molecular mechanisms of the selectivity of many proteostatic pathways remain incompletely understood. The overall goal of our research program is to investigate the mechanisms that determine the selectivity of proteostatic pathways by conducting functional analyses on proteome-wide scales. As a first step towards this long-term objective, we have focused on investigating the global selectivities of the macroautophagy pathway and methionine sulfoxide reductases. Macroautophagy can selectively target specific proteins and organelles for lysosomic degradation. Using novel proteomic approaches, we have identified subsets of proteins that rely on macroautophagy for their constitutive turnover. We have also shown that selective autophagic degradation plays a major role in maintaining protein homeostasis in quiescent cells and that alterations in autophagic flux is a pathologic feature of prion infected cells. Our future research will focus on understanding the molecular mechanisms of the differential selectivity of basal macroautophagy and investigating the prevalence and regulation of selective macroautophagy in quiescent and prion infected cells. The methionine sulfoxide reductase (Msr) system is an important repair pathway for oxidized methionine residues in proteins. To facilitate global analyses of the selectivity of Msrs, we have developed novel proteomic approaches for accurate quantitation of methionine oxidation on proteome-wide scales. Using these approaches, we plan to investigate the extent of methionine oxidation in proteomes of cells and tissues that are deficient in specific Msrs under normal and oxidative stress conditions. Together, the proposed experiments will provide insights into the mechanisms of client selection by macroautophagy and Msr pathways. Our studies will also examine the role of these two pathways in mitigating protein damage that occurs under specific proteotoxic stress conditions.

NIH Research Projects · FY 2026 · 2016-07

Osteoporosis (OP) is a global health concern with enormous socioeconomic burdens. Alarmingly, rates of osteoporosis screening using standard dual-energy x-ray absorptiometry (DXA) are abysmal, which contributes to high rates of preventable fragility fractures. Our long-term objective is to develop an accessible screening method based on Raman spectroscopy (RS) for early, accurate identification of at-risk patients during visits to primary care providers or community clinics. We posit that this would increase referrals for a gold standard DXA diagnosis and earlier interventions to reduce the incidence of preventable fragility fractures. We previously demonstrated the reliability and sensitivity of RS to detect biochemical changes associated with bone diseases in various mouse models and reported robust correlations of Raman spectral features with whole bone strength and fracture toughness. We also developed instrumentation and sophisticated algorithms to subtract optical contributions from overlying soft tissue to enable reliable diagnostically sensitive transcutaneous RS (tRS) of murine bone on intact limbs. As we pivot to scale up our instrumentation to make diagnostic measurements in humans, we are addressing three significant challenges. First, the ability to make reliable transcutaneous bone measurements is hampered by the signal from the thick layers of soft tissues that overlay the bone. Therefore, we identified the phalanges and metacarpals in the hand as anatomical sites suitable for tRS measurements, which can be accomplished by adjusting illumination source-detector offsets and establishing spectral libraries of various tissues. Second, there are no currently demonstrable associations between RS of peripheral bones of the hand and BMD at the clinically relevant sites of fragility fractures such as the wrist, hip, and spine. Third, there is currently no evidence that RS of bone can be safely and reliably acquired in living subjects for bone health diagnosis. In Aim 1, we will adapt our group’s novel spectral unmixing algorithm, SOLD, to apply it to a recently acquired dataset of human cadaver hand tRS measurements. The adaptation will account for spatial heterogeneities in Raman spectral responses at the midshaft versus the epiphyseal regions. In Aim 2 we will demonstrate diagnostic associations between tRS measurements in the phalanges and metacarpals of cadaver hands with clinically relevant wrist and hip DXA T-scores and wrist fracture risk. The cadaver hands will be obtained from donors with different sexes, ages, races, BMI, and DXA BMD and T-scores. In Aim 3, we will launch a pilot in vivo tRS study on 50 volunteers to improve methodology, identify differences from cadaver data, and perform fracture risk estimations directly from the tRS data. The proposed studies represent essential steps to demonstrating proof-of-concept of transcutaneous Raman spectroscopy as a clinically relevant diagnostic and prescreening tool for osteoporosis. Successful completion of the project will lay the foundation for future clinical studies.

NIH Research Projects · FY 2026 · 2016-05

Corticothalamic circuits linking the primary sensory cortex with the primary sensory thalamus in the feedback direction are ubiquitous across sensory modalities and mammalian species and are ideally positioned to regulate the flow of sensory signals from periphery to cortex. However, the functional role of these circuits in sensory perception remains a fundamental mystery in neuroscience. In the visual system, corticogeniculate neurons provide the majority of inputs onto neurons in the dorsal lateral geniculate nucleus (LGN), however receptive fields of LGN neurons closely resemble their retinal inputs and not their corticogeniculate inputs. Partly because corticogeniculate influence over LGN activity is modulatory rather than driving, the functional role of corticogeniculate feedback in vision has been difficult to characterize. The overarching goal of this proposal is to elucidate the structural organization of corticogeniculate feedback and its functional role in visual perceptual behavior. To accomplish this goal, intersecting and emerging technologies are employed including functional ultrasound imaging, neurophysiological recording, optogenetics, and chemogenetics in two highly visual mammalian species: ferrets and macaque monkeys. Building upon our previous findings that corticogeniculate feedback regulates the timing and precision of LGN responses to visual inputs, the three Specific Aims of this proposal address important new questions regarding the function and connectivity of corticogeniculate feedback. Specific Aim 1 will examine whether corticogeniculate feedback regulates the temporal dynamics of LGN neurons uniquely, depending on the type of visual feature information they convey. Specific Aim 2 will examine the spatial extent of corticogeniculate influence over LGN population activity using a combination of functional ultrasound and optogenetics. Aim 2 will also examine the precise functional connectivity between individual corticogeniculate and LGN neurons to determine whether corticogeniculate circuits exert stream-specific influence on individual LGN neurons. A major motivation behind Specific Aims 1 and 2 is to determine whether corticogeniculate feedback regulates visual information transmission through the LGN in a stream-specific manner or whether corticogeniculate influence is more global and diffuse. Specific Aim 3 represents a significant step forward in understanding corticogeniculate function by testing how corticogeniculate circuits contribute to visual discrimination behavior. We have developed a novel virus-mediated gene delivery strategy that enables selective manipulation of corticogeniculate circuits via optogenetics or chemogenetics, applicable to long-term behavioral experiments in ferrets. Together, results of the experiments proposed under each Aim will provide a fuller picture of the functional role of corticogeniculate feedback in visual perception by revealing the underlying connectivity and mechanisms giving rise to these functions. Importantly, insights gained about corticogeniculate circuit function could generalize across corticothalamic and corticocortical pathways throughout the sensory system and inform understanding of sensory circuit disruptions associated with many neurological disorders.

NIH Research Projects · FY 2022 · 2015-09

DESCRIPTION (provided by applicant): Over the last decade, the most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against the human epidermal growth factor receptors (HER1 and HER2) and therapies for hormone-receptor-positive disease. In combination with adjuvant chemotherapy, drugs such as trastuzumab (anti-HER2 antibody) or tamoxifen (hormone therapy) have significantly reduced relapses and increased disease-free survival in patients with metastatic disease. However, despite an initial positive response, the majority of patient's exhibit resistance - rendering the therapy ineffective within one year of treatment. Increased expression and hyperactivation of the insulin-like growth factor 1 receptor (IGF-1R) and its associated downstream signaling components (MAPK-PI3K/Akt/mTOR- IAP) have been implicated in this de novo and acquired resistance. Therefore, identification of novel targets and antineoplastic agents that modulate IGF-1R signaling is paramount. We have recently identified soluble E-cadherin, termed sEcad, as a novel oncogenic target that is selectively increased in human breast cancers. Additionally, we have discovered that sEcad imparts its tumorigenic effects (enhances proliferation, migration and invasion) by activating many of these resistance pathways, including IGF-1R and downstream MAPK-PI3K/Akt/mTOR-IAP signaling. More importantly, using a purified IGF-1R holoreceptor, we are the first to discover that sEcad acts as a true ligand for IGF-1R and in the presence of its natural ligand IGF-1 synergistically increases IGF-1R phosphorylation. Furthermore, we have evidence that sEcad synergizes with the high-affinity HER and IGF-1R ligands, IGF1 and EGF, to promote cancer cell proliferation, migration and invasion in vitro and act as an oncogenic driver in xenograft tumors in vivo. Therefore, we propose that sEcad is a valid and innovative therapeutic target for breast cancer. Additionally, we have recently tested region-specific antibodies against sEcad that successfully suppressed HER2+ and hormone-receptor positive breast cancers by directly inducing tumor cell death (apoptosis and necrosis), via down-regulating the IGF-1R, HER and MAPK-PI3K/Akt/mTOR-IAP axis. In trastuzumab-resistant breast cancer xenografts (which endogenously overexpress IGF-1R) and MMTV-PyMT mice, our studies demonstrate that targeted inhibition of sEcad successfully reduced tumor burden by inhibiting proliferation and inducing cell death. Consistent with the in vivo findings, this targeted therapy inhibited proliferation and directly induced apoptosis and necrosis in hormone-receptor-positive and trastuzumab-resistant breast cancer cells, without showing any off-target cytotoxic effects in normal cells. In this translational study, we have assembled an outstanding research team to: 1) biochemically and biophysically characterize the sEcad-IGF-1R interactions; 2) determine whether targeted inhibition of sEcad suppresses IGF-1R expressing breast cancers in vitro and in vivo; 3) gain mechanistic insights into how the antibody functions to down-regulate the IGF-1R axis; and 4) perform rodent efficacy, PK/PD studies and evaluation of off-target effects. Of note, although monoclonal antibodies against IGF-1R have given mixed results in clinical trials, these anti-sEcad antibodies potentially represent a completely different class of IGF1R inhibitors, with a very unique and innovative targeting mechanism.