R01MD016401

Jak-Stat Inhibition to Reduce Racial Disparities in Kidney Disease - Project Summary/Abstract

Disparities in kidney health is an important long-standing problem in the US. African Americans (AAs) who represent 13% of the US population, develop end-stage kidney disease (ESKD) at 3.5-fold higher rates than European Americans, explaining why 31% of people with ESKD are AAs. Two protein coding mutations in the apolipoprotein L1 (APOL1) gene are the causal drivers of 70% of this excess risk of ESKD in AAs. Despite the urgent need for treatment of APOL1-associated kidney disease (AAKD), there have not been any therapeutic trials specifically focused on AAKD. This need is compounded by severe underrepresentation of AAs in clinical trials. Until these needs are met, disparities in kidney health in the US will persist.

Our long-term goal is to develop targeted therapies for the two most common forms of AAKD: APOL1-associated focal segmental glomerulosclerosis (FSGS) and hypertension-induced chronic kidney disease (HTN-CKD) in order to mitigate the disparate burden of ESKD among AAs. The objective of this particular application is to target a proximal pathway that drives APOL1-induced podocyte injury, which is a central mechanism of AAKD. Our central hypothesis is that inhibition of JAK1 and JAK2 kinases will block APOL1-induced podocyte injury and proteinuria, and thereby mitigate progression of AAKD to ESKD. This hypothesis has been formulated on the basis of preliminary data produced in the applicant's laboratories.

The rationale for the proposed research is that discovery of an effective treatment for AAKD will reduce disparities in ESKD incidence, the high cost of ESKD care, and the enormous loss of lives associated with ESKD - which is responsible for nearly as much loss of life-years as breast cancer in women and more loss of life-years than colorectal cancer in men. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) build the Durham Community APOL1 Program for community engagement and translational research; 2) perform a pilot phase II randomized clinical trial of a clinically available JAK1/2 inhibitor in patients with AAKD; and 3) conduct an ex vivo clinical trial "in-a-dish" using induced pluripotent stem cell-derived podocytes (iPods) of AA patients with FSGS and HTN-CKD.

Our approach is innovative because it leverages a creative community engagement strategy to address the critical problem of underrepresentation of AAs in clinical trials while simultaneously studying the efficacy and safety of an innovative treatment for AAKD. It also leverages our innovative iPod platform as a tool for individualized therapy. The proposed research is significant because it is expected to serve as the basis for a future phase III trial of JAK1/2 inhibitor as therapy for AAKD. The impact of therapy for AAKD includes reduction of the disparate burden of ESKD, mortality, and financial cost associated with AAKD, which are priorities of NIDDK. Additionally, because of its ability to predict a patient's future clinical response to a drug, the iPod platform strives to advance personalized therapy of AAKD from theory to reality.

Duke University

TO SUPPORT BASIC, CLINICAL, SOCIAL, AND BEHAVIORAL RESEARCH, PROMOTE RESEARCH INFRASTRUCTURE AND TRAINING, FOSTER EMERGING PROGRAMS, DISSEMINATE INFORMATION, AND REACH OUT TO MINORITY AND OTHER HEALTH DISPARITY COMMUNITIES. THE NATIONAL INSTITUTE ON MINORITY HEALTH AND HEALTH DISPARITIES (NIMHD) HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS: (1) THE CENTERS OF EXCELLENCE PROGRAM PROMOTES RESEARCH TO IMPROVE MINORITY HEALTH AND/OR REDUCE AND ELIMINATE HEALTH DISPARITIES, BUILDS RESEARCH CAPACITY FOR MINORITY HEALTH AND HEALTH DISPARITIES RESEARCH IN ACADEMIC INSTITUTIONS, ENCOURAGES PARTICIPATION OF HEALTH DISPARITY GROUPS AND COMMUNITIES IN BIOMEDICAL AND BEHAVIORAL RESEARCH AND PREVENTION AND INTERVENTION ACTIVITIES, AND BRINGS TOGETHER INVESTIGATORS FROM RELEVANT DISCIPLINES IN A MANNER THAT WILL ENHANCE AND EXTEND THE EFFECTIVENESS OF THEIR RESEARCH, (2) NIMHD RESEARCH ENDOWMENT PROGRAM BUILDS RESEARCH CAPACITY AND INFRASTRUCTURE AT ELIGIBLE NIMHD CENTERS OF EXCELLENCE OR ELIGIBLE SECTION 736 HEALTH PROFESSIONS SCHOOLS (42 U.S.C. 293) TO FACILITATE MINORITY HEALTH AND OTHER HEALTH DISPARITIES RESEARCH TO CLOSE THE DISPARITY GAP IN THE BURDEN OF ILLNESS AND DEATH EXPERIENCED BY RACIAL AND ETHNIC MINORITY AMERICANS AND OTHER HEALTH DISPARITY POPULATIONS, PROMOTES A DIVERSE AND STRONG SCIENTIFIC, TECHNOLOGICAL AND ENGINEERING WORKFORCE, AND EMPHASIZES THE RECRUITMENT AND RETENTION OF UNDERREPRESENTED MINORITIES AND OTHER SOCIO-ECONOMICALLY DISADVANTAGED POPULATIONS IN THE FIELDS OF BIOMEDICAL AND BEHAVIORAL RESEARCH AND OTHER AREAS OF THE SCIENTIFIC WORKFORCE, (3) THE CENTERS OF EXCELLENCE ON ENVIRONMENTAL HEALTH DISPARITIES RESEARCH TO STIMULATE BASIC AND APPLIED RESEARCH ON ENVIRONMENTAL HEALTH DISPARITIES, (4) MINORITY HEALTH AND HEALTH DISPARITIES INTERNATIONAL RESEARCH TRAINING PROGRAM (MHIRT) AWARDS ENABLE U.S. INSTITUTIONS TO TAILOR SHORT-TERM BASIC SCIENCE, BIOMEDICAL AND BEHAVIORAL MENTORED STUDENT INTERNATIONAL RESEARCH TRAINING OPPORTUNITIES TO ADDRESS GLOBAL ISSUES RELATED TO UNDERSTANDING, REDUCING, AND ELIMINATING HEALTH DISPARITIES, (5) SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM INCREASES PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, ENCOURAGES SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTERS AND ENCOURAGES PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (6) SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTERS TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, INCREASES PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTERS AND ENCOURAGES PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (7) HEALTH DISPARITIES RESEARCH PROJECT GRANTS (RPG) SUPPORT INNOVATIVE PROJECTS TO ENHANCE OUR UNDERSTANDING OF BIOLOGICAL MECHANISMS, SOCIAL, BEHAVIORAL, AND HEALTH SERVICES THAT CAN DIRECTLY AND DEMONSTRABLY CONTRIBUTE TO THE IMPROVEMENT IN MINORITY HEALTH AND THE ELIMINATION OF HEALTH DISPARITIES WHICH INCLUDES THE (8) RESEARCH CENTERS IN MINORITY INSTITUTIONS (RCMI) BUILD CAPACITY FOR BASIC BIOMEDICAL AND/OR BEHAVIORAL RESEARCH, CLINICAL AND TRANSLATIONAL RESEARCH (RCTR) AND A NETWORK (RCTN) BY FOCUSING ON INSTITUTIONAL RESOURCE DEVELOPMENT, SUCH AS SUPPORTING CORE RESEARCH FACILITIES AND STAFF, PURCHASING ADVANCED INSTRUMENTATION, AND LABORATORY RENOVATIONS/ALTERATIONS (9) CLINICAL RESEARCH EDUCATION AND CAREER DEVELOPMENT (CRECD) AWARDS PROVIDE DIDACTIC TRAINING AND MENTORED CLINICAL RESEARCH EXPERIENCES TO DEVELOP INDEPENDENT RESEARCHERS WHO CAN LEAD CLINICAL RESEARCH STUDIES, ESPECIALLY THOSE ADDRESSING HEALTH DISPARITIES, (10) PATHWAY TO INDEPENDENCE AWARDS (K99/R00) TO INCREASE AND MAINTAIN A STRONG COHORT OF NEW AND TALENTED, NIH-SUPPORTED, INDEPENDENT INVESTIGATORS. (11) NIH RESEARCH CONFERENCE GRANT AND NIH RESEARCH CONFERENCE COOPERATIVE AGREEMENT PROGRAMS SUPPORT HIGH-QUALITY CONFERENCES THAT ARE RELEVANT TO THE MINORITY HEALTH AND HEALTH DISPARITIES, (12) TRANSDISCIPLINARY COLLABORATIVE CENTERS FOR HEALTH DISPARITIES RESEARCH COMPRISE REGIONAL COALITIONS OF ACADEMIC INSTITUTIONS, COMMUNITY ORGANIZATIONS, SERVICE PROVIDERS AND SYSTEMS, GOVERNMENT AGENCIES AND OTHER STAKEHOLDERS CONDUCTING COORDINATED RESEARCH, IMPLEMENTATION AND DISSEMINATION ACTIVITIES THAT TRANSCEND CUSTOMARY APPROACHES AND SILO ORGANIZATIONAL STRUCTURES TO ADDRESS CRITICAL QUESTIONS AT MULTIPLE LEVELS IN INNOVATIVE WAYS FOCUSED ON PRIORITY RESEARCH AREAS IN MINORITY HEALTH AND HEALTH DISPARITIES, (13) RUTH L. KIRSCHSTEIN NRSA INDIVIDUAL PREDOCTORAL FELLOWSHIP

93.307 - Minority Health and Health Disparities Research

National Institute for Minority Health and Health Disparities (NIMHD) [HHS - NIH]

Durham, North Carolina 27705 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the total obligations have increased 421% from $676,165 to $3,524,489.