Grants

National Institutes of Health

Clinical Observational (CO) Studies in Musculoskeletal, Rheumatic, and Skin Diseases (R01 Clinical Trial Not Allowed)

NIDCR - National Institute of Dental and Craniofacial Research

The objective of this contract renewal is to continue operations and management support services for clinical research studies supported by the National Institute of Dental and Craniofacial Research (NIDCR) within both the extramural and intramural research divisions. The contract provides staff with tools essential for the effective administration and coordination of NIDCR’s clinical studies. It provides technological support for the maintenance and updates to the custom NIDCR-Clinical Research Management System (CRMS). In addition, it provides adjunct expertise and resources to assure sound and efficient clinical study documentation, clinical site monitoring, and data and safety monitoring support. Specific tasks performed varies by clinical study.

FIC - John E. Fogarty International Center for Advanced Study in the Health Sciences

PROJECT SUMMARY/ABSTRACT The burden of prostate cancer diagnosis and its mortality in Nigeria is high. Delay in patient presentation to urologists at tertiary healthcare facilities is a major challenge, resulting in diagnosis with advanced disease and suboptimal quality of life of patients. Despite this challenge, optimal screening is hampered by the low specificity of prostate specific antigen for the detection of clinically significant prostate cancer leading to unnecessary biopsies and overdiagnosis. To combat this problem, prostate cancer clinical risk calculators have been deployed to identify men at high risk of clinically significant disease. These risk calculators have variable predictive values across different populations. The Rotterdam Risk Calculator and Prostate Biopsy Collaborative Group Risk Calculator have been extensively validated in the European ancestry population. The Mistry-Sun Risk Calculator is however better calibrated for U.S. Black men. None of these tools has been validated for the Nigerian population. Moreover, very few prostate cancer risk calculators can be readily used at community-level hospitals. As human and material resource availability for prostate cancer risk assessment varies between urologists and primary care providers and between Nigeria and other countries, foundational research should focus on developing and implementing contextually appropriate models “Naija risk calculators” that will be easy to integrate into Nigerian clinical practice. To address this gap, this mentored research proposal aims to: (1) compare the accuracy of existing risk calculators for predicting clinically significant prostate cancer in a prospective cohort of Nigerian men; (2) develop tailored multinomial regression models for the prediction of clinically significant prostate cancer in Nigeria; and (3) conduct a pilot implementation trial of a risk calculator to optimize community-based Prostate Cancer Early Detection Intervention in Nigeria. To achieve these aims, Dr. Tolani will leverage existing research partnerships in Nigeria, and a unique multidisciplinary team of mentors with necessary research expertise for the Nigerian prostate cancer context, prediction modeling, implementation science and global oncology. The proposed research will result in validated risk calculators that can be feasible to implement in a future R01 hybrid trial of a primary care provider-facing risk calculator in a refined Prostate Cancer Early Detection Intervention. This K43 award will also support advanced training in: (1) statistical methods for diagnostic tool evaluation; (2) clinical prediction modeling; (3) implementation science study designs; and (4) global oncology leadership. For each goal, Dr. Tolani will complete courses, mentored tutorials, and experiential learning from the research aims. This training will position Dr. Tolani for a successful independent career in precision-informed early and optimal prostate cancer detection and global oncology, advancing his ultimate goal of addressing cancer disparities through team science and collaborations in Nigeria and beyond.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

(PLEASE KEEP IN WORD, DO NOT PDF) Telomere biology disorders (TBD) are multisystem disorders caused by premature shortening of telomere lengths. Hematopoietic stem and progenitor cells (HSPC) in TBD show impaired proliferative capacity manifesting as bone marrow failure (BMF). We and others have shown that HSPCs from TBD patients may develop somatic mosaic events that lead to context-specific clonal hematopoiesis (CH), overcoming replicative constraints. Due to TBD-specific unique stressors, these patients have a higher prevalence of CH (40% vs. 6% in age-matched non-TBD individuals) and a characteristic context-specific mutational spectrum mainly in DNA damage response and repair (DDRR) pathways and the p.S34 position in the spliceosome gene U2AF1, which results in multiple missplicing events. U2AF1MT-S34 is associated with rapid clonal expansion and evolution to myeloid neoplasm in non-TBD population, but TBD-U2AF1MT-S34 patients show a perplexing stability over time. This suggests that clonal dynamics and clinical outcomes of CH in TBD differ from age-related CH, with the underlying mechanisms behind these differences still unknown. We hypothesize that U2AF1MT-S34 somatic events result in splicing alterations in key pathways that rescue hematopoiesis in the context of TBD and may lead to adaptive and/or maladaptive outcomes, including progression to myeloid neoplasm. To test this, we will create and characterize a new K562 hematopoietic stem cell line to study our preliminary observations in TBD patients with U2AF1MT-S34 CH. In Aim 1, we will use a novel CRISPR/Cas9 method developed in our laboratory to create a K562 TERTMT cell line. We have used this method successfully in HEK-293t cells resulting in a phenotype that resembles TBD (low telomerase activity, short telomeres, replicative impairment). Using the same approach, we will introduce the U2AF1MT-S34 variant in this K562 TERTMT cell line and characterize the effect of these co-occurring mutations on telomere length, replicative capacity and morphology. In Aim 2, we will characterize the transcriptomic missplicing changes exerted by U2AF1MT-S34 in relevant pathways (DDRR, splicing, and telomere maintenance) in the context of short telomeres using long-read RNA sequencing (Oxford Nanopore). This project offers both conceptual and methodological innovation by creating a new model of TBD-CH and using it to characterize the downstream effect of the most frequent somatic event observed in these patients.

NIA - National Institute on Aging

As people living with HIV (PWH) reach older age, determining their risk for mild cognitive impairment (MCI) and Alzheimer’s disease and related dementias (ADRDs) is emerging as a major public health priority. Because HIV is relatively rare in the United States, particularly in the elderly, data in this area have largely been limited to young populations and lacked large samples with brain imaging and biomarkers to determine disease phenotypes. Moreover, social and clinical health predictors of MCI/ADRD differ meaningfully in PWH, so risk factors and their impact on households cannot be extrapolated from other populations. To respond to these gaps, we will leverage a team of experts in HIV epidemiology, diagnosis and phenotyping of MCI/ADRDs with fluid and imaging biomarkers, and machine learning (ML), and a large and well-established cohort of older people with HIV. Preliminary data generated by our team include neuropsychological screening of 300 older virologic suppressed PWH in Uganda (mean age >60), and 300 demographically similar people without HIV, showing that >30% of PWH have characteristics of MCI and that brain MRI and ML techniques add critical phenotyping data to standard batteries. Four specific aims are proposed: Aim 1: Determine the prevalence and classification of MCI/ADRDs (1A) and compare trajectories of cognitive performance (1B) between older PWH and similar people without HIV. Comprehensive neuropsychological assessments will be completed in older adults with and without HIV in the cohort (n=600) annually during years 1-4. MCI/ADRDs will be identified using multi-disciplinary case consensus criteria to provide diagnoses and underlying etiologies. Aim 2: Identify pathophysiologic contributors to MCI/ADRDs in older adults through deep phenotyping with novel plasma biomarkers and neuroimaging. Assessments will include Aβ42/Aβ40, p-tau217, GFAP, and NfL biomarkers and brain MRIs to characterize phenotypes. Aim 3: Estimate the psychosocial and economic impacts of MCI/ADRDs on adult household members. We will conduct in-depth interviews (n~40, Aim 3A) to learn about lived experiences of caregivers, and quantitative surveys (Aim 3B) to all adult household members of the cohort (n~1800) on employment and resource use, caregiving burden, quality of life, stigma, social participation, loneliness, and mental health. We will compare participants by the presence vs absence of MCI/ADRDs in the household. Aim 4: Discover and validate novel, multilevel mechanistic models of MCI/ADRDs among older PWH by employing ML methods with the full array of data collected in Aims 1-3. We will determine which combinations of highly dimensional features reliably classify individuals according to MCI/ADRDs profiles. Completing these aims will advance our understanding of MCI/ADRDs epidemiology among older PWH. In doing so, it will lay the foundation for diagnostic and intervention efforts to address research priorities for PWH in the United States and beyond.

NIA - National Institute on Aging

As people living with HIV (PWH) reach older age, determining their risk for mild cognitive impairment (MCI) and Alzheimer’s disease and related dementias (ADRDs) is emerging as a major public health priority. Because HIV is relatively rare in the United States, particularly in the elderly, data in this area have largely been limited to young populations and lacked large samples with brain imaging and biomarkers to determine disease phenotypes. Moreover, social and clinical health predictors of MCI/ADRD differ meaningfully in PWH, so risk factors and their impact on households cannot be extrapolated from other populations. To respond to these gaps, we will leverage a team of experts in HIV epidemiology, diagnosis and phenotyping of MCI/ADRDs with fluid and imaging biomarkers, and machine learning (ML), and a large and well-established cohort of older people with HIV. Preliminary data generated by our team include neuropsychological screening of 300 older virologic suppressed PWH in Uganda (mean age >60), and 300 demographically similar people without HIV, showing that >30% of PWH have characteristics of MCI and that brain MRI and ML techniques add critical phenotyping data to standard batteries. Four specific aims are proposed: Aim 1: Determine the prevalence and classification of MCI/ADRDs (1A) and compare trajectories of cognitive performance (1B) between older PWH and similar people without HIV. Comprehensive neuropsychological assessments will be completed in older adults with and without HIV in the cohort (n=600) annually during years 1-4. MCI/ADRDs will be identified using multi-disciplinary case consensus criteria to provide diagnoses and underlying etiologies. Aim 2: Identify pathophysiologic contributors to MCI/ADRDs in older adults through deep phenotyping with novel plasma biomarkers and neuroimaging. Assessments will include Aβ42/Aβ40, p-tau217, GFAP, and NfL biomarkers and brain MRIs to characterize phenotypes. Aim 3: Estimate the psychosocial and economic impacts of MCI/ADRDs on adult household members. We will conduct in-depth interviews (n~40, Aim 3A) to learn about lived experiences of caregivers, and quantitative surveys (Aim 3B) to all adult household members of the cohort (n~1800) on employment and resource use, caregiving burden, quality of life, stigma, social participation, loneliness, and mental health. We will compare participants by the presence vs absence of MCI/ADRDs in the household. Aim 4: Discover and validate novel, multilevel mechanistic models of MCI/ADRDs among older PWH by employing ML methods with the full array of data collected in Aims 1-3. We will determine which combinations of highly dimensional features reliably classify individuals according to MCI/ADRDs profiles. Completing these aims will advance our understanding of MCI/ADRDs epidemiology among older PWH. In doing so, it will lay the foundation for diagnostic and intervention efforts to address research priorities for PWH in the United States and beyond.

National Institutes of Health

Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (R21 Clinical Trial Not Allowed)

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT In this grant cycle, Rutgers Cancer Institute had an unprecedented opportunity to expand clinical research to a significant number of additional hospitals of the RWJBarnabas Health (RWJBH) system. This unified and organized expansion was enabled by 1) Dr. Libutti’s roles as Cancer Center Director and Senior VP for Oncology Services of RWJBH; 2) Dr. Hochster’s roles as Rutgers Cancer Institute Associate Director for Clinical Research and Director of Oncology Research for RWJBH; and 3) development of a system-wide academic health system between Rutgers and RWJBH effective 01/01/2019 through a Master Affiliation Agreement. In this newly integrated and unified “one-site” model, Rutgers Cancer Institute has an unprecedented number of patients at its disposal for clinical research activities to impact the catchment areas' priorities and needs positively. The Office of Human Research Services (OHRS) serves as a centralized research administration, housing all administrative tasks at Rutgers Cancer Institute while providing oversight and direction for each clinical oncology research operation site throughout RWJBH. OHRS is responsible for working with Rutgers and system-wide clinical investigators to manage the business, clinical, and regulatory functions of all phases of pediatric and adult oncology cancer clinical trials throughout the health system. Our model is “one site with one CTMS, one IRB, and one EMR’, which is currently operational. The organizational structure, which reports to Drs. Libutti and Hochster is comprised of 158 FTEs with ten distinct offices divided and based on specialization within functional areas such as clinical operations, quality assurance, and regulatory affairs. In parallel with the growth of Rutgers Cancer Institute, screening, enrollment, and the number of available NCTN clinical trials increased significantly with the integration of RWJBH health system sites into OHRS. To date, the number of open trials has more than doubled (52 vs. 24 in 2019), and enrollments in NCTN clinical trials have increased by more than 500% (662 vs. 132). Minority enrollment has steadily increased from 29.9% in 2019 to 41.3% in 2024 over the grant period. During the current grant period, therapeutic trial accrual has risen by more than 400% (552 vs.132). In recent years, Rutgers investigators have held prominent roles within ECOG-ACRIN, NRG, and Alliance. Evidence of our success in scientific contributions is reflected in our investigators' significant leadership roles, memberships in key group studies, and authorship of numerous publications stemming from NCT trial participation. Moreover, Rutgers consistently mentors and engages young investigators in clinical trial research, as demonstrated by the recent appointment of two junior investigators who have assumed leadership roles in ECOG-ACRIN clinical trials.

NCI - National Cancer Institute

The planned activities describe a set of efforts that will build upon my primary interest in brain tumors, leveraging my experience and leadership roles to develop national clinical trials, implement NCI-sponsored trials at the NCI-designated P30 Herbert Irving Comprehensive Cancer Center (HICCC), and continue to provide service to the NCI Clinical Trials Network (NCTN) among other efforts. I have dedicated nearly 25 years of service to NCI-sponsored clinical trials as a member of the Brain Tumor and later Brain Tumor Core Committees of NRG Oncology (and seeking to become the new Brain Tumor Committee Chair) and its predecessor, the Radiation Therapy Oncology Group. I have served as national PI/overall Study Chair for multiple RTOG/NRG Oncology sponsored trials, represented the Brain Tumor Core Committee at the NRG Oncology grant planning retreat, and represent NRG Oncology itself on the NCI Brain Malignancies Steering Committee. At Columbia University Irving Medical Center, I serve as HICCC Associate Director (AD) for Clinical Trials, overseeing the HICCC clinical trial infrastructure with 125 full-time research professionals supporting > 70 HICCC members conducting > 400 oncology studies. I am also a member of the HICCC Director’s Leadership Team. Receiving this grant will afford me an opportunity to: (1) develop innovative HICCC Investigator-led NCTN trials; (2) expand the NCTN, Experimental Therapeutics Clinical Trials Network (ETCTN, Yale as coordinating center), and NCI Community Oncology Research Program (NCORP) trial portfolio for all disease sites at HICCC and its affiliated hospitals; (3) mentor the next generation of oncology translational scientists. I will continue to bring NCTN trials to HICCC and our NCORP subcomponent sites, drawing on my previous experience as co-principal investigator on NCORP grant. To enhance accrual I will collaborate with our Community Outreach and Engagement office and Vice Dean of Community Health to facilitate new programs including the Clinical Trials Training Program (CTTP), a didactic course (3 months) that aims to educate current and future investigators in the conduct of clinical trials. It is part of a broader initiative dedicated to increased trial accrual, such as by identifying and overcoming barriers to clinical trial participation. Finally, as HICCC AD for Clinical Trials, I am mentoring the next generation of investigators, including our site PIs who represent the HICCC in the NCTN, ETCTN, and NCORP. Buttressed by an exceptional team, advisors, and institutional support, I am poised to expand my professional perspective and elevate my academic achievements that fulfill the NCI R50 goals and objectives.

National Institutes of Health

Clinical Validation of a Candidate Biomarker for Neurological or Neuromuscular Disorders (U01 Clinical Trial Optional)

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Hypertension is a major cause of premature death globally, responsible for 10.4 million deaths annually. Around 1.28 billion adults aged between 30-79 worldwide have hypertension, of which only 1 in 5 adults (21%) have it under control. Hypertension is diagnosed when blood pressure (BP) is consistently ≥130 (systolic BP (SBP)) and/or ≥80 mmHg (diastolic BP (DBP)). It is associated with both an increased risk of cardiovascular disease (CVD) and reduced life expectancy. The prescribed first line of hypertension drugs belongs to the thiazide diuretics, calcium antagonists, angiotensin converting enzyme (ACE) and angiotensin receptor blockers (ARB) classes of drugs. Other diuretics and beta blockers are considered secondary either due to safety and tolerability issues or due to weaker clinical outcomes. According to the American Heart Association (AHA) and the American College of Cardiology (ACC) 2018 hypertension guidelines, the on-treatment target BP is <130/80 mmHg. In general, at least 2 antihypertensive drugs with different mechanisms of action are required to achieve proper BP control. However, in spite of the multiple classes of drugs, efficient BP control is only achieved in 30.4% of treated adults. NuSirt Sciences, Inc. (NuSirt) developed a fixed dose combination (FDC) of L-leucine, metformin and sildenafil (NS-0200) as a hypertensive drug with potential to improve other cardiometabolic risk factors (bodyweight (BW), hyperlipidemia and glycemic control). L-leucine with low doses of metformin and sildenafil activates the Sirt1/AMPK/eNOS energy metabolism pathway thereby modulating Sirt1-dependent metabolism and serving as a partial mimetic of calorie restriction on BP regulation. In the present SBIR Phase II project, NuSirt will manufacture NS-0200 under GMP conditions to conduct a 12-week randomized clinical trial on hypertensive adults to determine the efficacy of the drug in controlling BP compared to placebo. Primary endpoint analysis will be the evaluation of change in mean seated SBP from baseline to study termination. Secondary endpoint analysis will comprise the evaluation of change in DBP and body weight. Exploratory analysis will consist of assessing the effect of NS-0200 on blood glucose and lipid levels. Safety will be assessed throughout the study by examination of adverse events (AE), concomitant medications, clinical laboratory evaluations, vital signs, physical examinations and 12-lead ECGs. Completion of this SBIR Phase II will serve as a foundation to pursue a Phase III clinical program, aiming to compare the efficacy of NS-0200 with other hypertension drugs currently available in the market.

NIA - National Institute on Aging

PROJECT SUMMARY. Neurodegenerative diseases are currently defined by the clinical symptoms observed antemortem (i.e., dementia syndrome), patterns of anatomic atrophy, and cellular and molecular pathology confirmed postmortem. A key challenge in this field is the fact that a single dementia syndrome can be caused by multiple pathologies, and the same pathology can manifest as multiple dementia syndromes. The “Type C” variant of frontotemporal lobar degeneration due to TDP (TDP-C) pathology is unique. TDP-C shows a strong affinity for the anterior temporal lobe (ATL), a brain region critical for word knowledge. TDP-C also has an uncommonly tight coupling with semantic primary progressive aphasia (PPA-S), a dementia syndrome defined by initial decline primarily in semantic (i.e., word knowledge) abilities and atrophy of the ATL in the left language hemisphere; nearly 90% of PPA-S cases show TDP-C at death. The association of selective ATL atrophy, TDP- C pathology, and semantic language impairment in PPA-S offers an ideal paradigm to examine anatomic language networks, mechanisms of neurotoxicity, and principles of selective vulnerability. A central hypothesis is that atrophy patterns in PPA-S mirror underlying neurodegenerative changes due to TDP-C, leading to dysfunction in neurocognitive networks critical for semantics. The proposed research will characterize and clarify relationships between clinical symptoms, atrophy, and underlying pathological substrates in PPA-S due to TDP- C. Aim 1 of this study focuses on identifying the anatomic signature unique to semantic language impairment progression seen in PPA-S due to TDP-C. It is hypothesized that this progression is defined by progressive atrophy along the temporal lobe of the left language hemisphere. Longitudinal neuropsychological testing will categorize TDP-C individuals into discrete stages of semantic language impairment. Volume loss will be assessed using voxel-based morphometry, comparing whole brain volume and specific regions of interest (ROIs) along the temporal lobe in TDP-C participants to a cognitively healthy group at and between impairment stages. The goal of Aim 2 is to examine the clinicopathologic relationship between antemortem patterns of atrophy and postmortem pathologic markers in the temporal lobe in PPA-S. It is expected that regional and hemispheric densities of markers will mirror the aphasic phenotype and atrophy pattern in PPA-S. Using whole hemisphere sections, pathologic inclusions, neuronal and synaptic integrity, and neuroinflammatory (microglia) markers will be quantified in bilateral ROIs used in Aim 1 using unbiased stereology and digital pathology methods. This project will occur within the Northwestern University Alzheimer’s Disease Research Center, a multidisciplinary, international PPA referral center that holds the world’s largest cohort of TDP-C participants with extensive longitudinal clinical, neuroimaging, and neuropathologic data. The public health impact of this study is significant, as studies of TDP-C have the potential to address questions about dysfunction due to neurodegenerative pathology and inform future development of disease-specific biomarkers and therapeutic targets.

NIAID - National Institute of Allergy and Infectious Diseases

Xenotransplantation (XTx) represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. We have recently reported consistent >8 months survival in consecutive cases of pig-to-baboon kidney xenotransplantation (KXTx) using source pigs with 10 genetic modifications. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation (KXTx) and resulted in FDA clearance of the first-ever human clinical trial of a xenoorgan. However, these studies also identified new challenges that will need to be addressed to ensure safe clinical translation of preclinical data in xenotransplantation. The overall goal of this project is to address these remaining issues, to elucidate underlying mechanisms of graft loss and injury, and to test novel targeted strategies with the goal of facilitating clinical translation of XTx with consistent and durable graft survival. Accordingly, we have outlined the following specific aims: (1) to optimize a clinically relevant immunosuppression regimen consisting of FDA-approved medications, targeting specific pathways involved in both early and late graft loss, and to characterize the risk of sensitization associated with xenotransplantation; and (2) to evaluate the impact of vascularized thymus co-transplantation on xenograft survival. We will attempt to prolong kidney xenograft survival with FDA-approved immunosuppression by combining innovative strategies: preventing the early graft injury that leads to long-term xenograft dysfunction by targeting evidence-based pathways involved in ischemia reperfusion injury and xeno-specific rejection, using multi-KO and transgenic source pigs, and including the immunomodulatory strategy of vascularized thymic transplantation. If successful, our approach could provide a virtually limitless supply of xenogeneic kidneys for human patients to meet the demands of the organ shortage, and may enable reduction or elimination of lifelong immunosuppression.

Regional Council Capital Fund - RC4

Clinician Education and Simulation Lab Capital

Clinton

Clinton County

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Economic Development

Clinton

Clinton County

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Clinton County Safe Swimming Initiative

DESPP

Clinton Public Works and Emergency Management Building