Richard D. Johnson - US grants

renal failure; renal glomerulus; hemolytic anemia; oncoprotein p21; cyclins; cell cycle proteins; transforming growth factors; enzyme inhibitors; fibroblast growth factor; apoptosis; neutralizing antibody; laboratory rat; laboratory mouse; immunocytochemistry; tissue /cell culture;

DESCRIPTION(provided by applicant): The goal of the proposed research training program is to prepare trainees for a successful academic research career by providing expert and comprehensive mentoring in laboratory or clinical research pertinent to kidney disease. The program proposed in this application has the faculty expertise, infrastructure, and research opportunities to provide outstanding training. The training program is organized into five thematic administrative units designed to provide greater interdisciplinary collaboration, adminstrative cohesiveness, and enhance research opportunities for trainees: the Core Nephrology Unit; the Diabetes, Human Genetics, and Gene Therapy Unit; the Glomerulonephritis and Renal Immunology Unit; the Stem Cell and Developmental Biology Unit; and the Clinical Research Training Unit. The program has thirty training mentors from different basic and clinical departments; the number of faculty has been increased substantially to provide a greater scope, depth and opportunities for interdisciplinary research in the basic sciences to accommodate the increasingly complex and technologic nature of research and the need to have greater participation of the basic sciences in the training of M.D. basic science investigators in nephrology. The research encompassed by the training program is highly pertinent to normal renal physiology and kidney disease. It includes the physiology, molecular biology and cell biology of tubular epithelial cells ion transport, the biochemistry of signaling pathways in kidney epithelia, the cell biology of the calcium receptor and other G-protein coupled receptors in renal epithelia, the early gene response to oxidative renal injury, the biochemical basis of renal tubular injury, and the cell biology and biochemistry of vascular endothelium. The training program also broadly encompasses the immunology, genetics, glomerular inflammation, and epithelial stem cell differentiation. Trainees will have full access to the entire graduate school curriculum, The clinical investigation program includes offering trainees the opportunity to apply for and enroll in the K30 APPCI program, which provides rigorous training in clinical epidemiology, biostatistics, outcomes research, study resign and a mentored clinical research program. Trainees are required to participate in a weekly formal research conference as well as weekly research-in-progress conferences in which both trainees and mentors responsible for supervision of research present their research.

[unreadable] DESCRIPTION (provided by applicant): Thiazide diuretics are associated with many metabolic side effects including hyperuricemia, gout, insulin resistance, and hyperlipidemia. These very conditions are already highly prevalent in African-Americans. We and others have generated a large body of epidemiologic, animal model, cell culture, and preliminary data in patients that suggests that uric acid is itself a mediator of hypertension, endotheliai dysfunction, and systemic inflammation. In our animal models elevated uric acid leads to increased blood pressure (BP) and lowering uric acid decreases BP. Furthermore, our study of hypertensive young adults suggests that allopurinol treatment leads to a decrease in uric acid associated with a lower BP. Our hypothesis is that thiazide-induced hyperuricemia decreases the efficacy of thiazides in controlling BP, leads to endothelial dysfunction, and increases the incidence of insulin resistance and impaired glucose tolerance. This hypothesis will be tested in a randomized double-blind placebo-controlled 2x2 factorial clinical trial of 8- week duration in which a total of 300 African-Americans patients with stage 1 hypertension (BP: 140-159/90- 99 mm Hg) will be assigned to one of four regimens: 1) a thiazide-like diuretic, chlorthalidone 25 mg/day, and a xanthine oxidase inhibitor, allopurinol; 2) chlorthalidone 25 mg/day and placebo; 3) placebo or 4) allopurinol. All subjects will receive a low-sodium diet. Our hypothesis predicts that lowering uric acid will enhance BP control, prevent endothelial dysfunction, reduce systemic inflammation, improve g.ucose tolerance and reduce hyperinsulinemia. In Aim 1 we test the hypothesis that prevention of chlorthalidone - induced hyperuricemia with allopurinol results in improved BP control. In Aim 2 we test the hypothesis that prevention of chlorthalidone-induced increase in serum uric acid by allopurinol improves endothelial function and reduces systemic inflammation. In Aim 3 we test the hypothesis that prevention of chlorthalidone induced hyperuricemia with allopurinol improves renal blood flow and GFR and prevents microalbumineria. [unreadable] [unreadable]

Description: Project Summary and Relevance There"remains a critical need for academic nephrologists to investigate the etiologies, pathogenesis, and management of kidney diseases. Kidney disease from hypertension and diabetes continue to increase at an alarming rate throughout the world; yet the number of individuals entering the field to conduct research continues to be inadequate. The objective of this training grant renewal is to provide superb training in basic, translational, or clinical research in the field of kidney diseases, hypertension, and renal transplantation. Training will be provided to both predoctoral (2 PhD or MD-PhD students) and postdoctoral (3 MDs or PhDs) fellows, for 2 to 3 years. Each trainee will conduct research and also attend didactic lectures. A large variety of research areas are available for study, including chronic kidney disease, hypertension, diabetic renal disease, glomerulonephritis, transplantation, acid-base and electrolyte transport, clinical investigation (outcomes, pharmacogenomics, and investigator-driven), as well as in basic sciences (molecular biology, cell signaling, or genetics). Trainees will each have a renal mentor, a nonrenal (basic science or clinical investigator) mentor, and a core mentor group. Forthose who enter clinical research an MPH in the School of Public Health or MS in Clinical Investigation can also be obtained. By the completion of their training all applicants will submit a summary of their research to their core mentor group, give Renal Grand Rounds, and prepare a grant application for future funding that is carefully evaluated by the training faculty. It is our belief that an organized, well focused program that orfers training across the full spectrum of basic to clinical research in nephrology will provide an attractive venue for the recruitment of promising individuals into a productive academic career. Relevance. A major consequence of the epidemic of obesity, metabolic syndrome, and diabetes has been a dramatic increase in the number of patients suffering from kidney disease. Currently there are over 10 million individuals with variable degrees of renal dysfunction, including nearly 800,000 with either end stage or near end stage renal disease. Yet, there is a critical shortage of academic nephrologists entering investigative careers. This training grant will support a focused program for training promising candidates in basic, translational, and clinical research which should help them prepare for an academic career in nephrology.

4H-Imidazol-4-one, 2-amino-1,5-dihydro-1-methyl-; Blood Pressure; Blood Pressure, High; Blood Serum; CREA; CRISP; Computer Retrieval of Information on Scientific Projects Database; Creatinine; Development; Dysfunction; ESRD; End stage renal failure; End-Stage Kidney Disease; Flow, Renal Blood; Functional disorder; Funding; Grant; Hypertension; INFLM; Inflammation; Institution; Investigators; Kidney; Kidney Diseases; Lead; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nephropathy; Non-smoker; Oxidative Stress; Pb element; Physiopathology; Proteinuria; Relative; Relative (related person); Renal Blood Flow; Renal Disease; Renal Disease, End-Stage; Renal function; Research; Research Personnel; Research Resources; Researchers; Resources; Risk Factors; Role; Secondary to; Serum; Smoke; Smoker; Smoking; Source; Tobacco; United States National Institutes of Health; Urinary System, Kidney; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; heavy metal Pb; heavy metal lead; hemodynamics; hyperpiesia; hyperpiesis; hypertensive disease; kidney disorder; kidney function; nonsmoker; novel; pathophysiology; renal; renal disorder; social role