BOLD MRI: Application to Intrarenal Oxygenation

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Hypertension, also known as high blood pressure, affects one in four adults in the United States, and is a major risk factor for stroke, heart attack and kidney disease. It is sometimes called the "silent killer" because it often has no symptoms. Progress towards preventing and curing hypertension has been impeded by a lack of thorough understanding of its underlying pathophysiology. Significant progress made over the last decade in vascular biology has allowed for better understanding of many of the underlying mechanisms, which then has led to development of novel drug treatments for hypertension. Many now believe that kidney plays an important role in the pathophysiology of hypertension. Specifically, it is thought that renal medullary blood flow has a direct influence on hypertension. It is still a topic of debate as to the alterations in the kidney being the cause or the consequence of hypertension. In either case, availability of a non-invasive method to probe blood flow at a regional level within the kidney would allow for verifying many of the hypotheses to be tested in humans. Based on previous experience with blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) technique to the kidney, we hypothesize that the technique would be sensitive to changes in medullary blood flow. More specifically, we believe that the technique in combination with suitable endothelium-dependent vasoactive agents would allow for renal microvascular reactivity studies to be performed in a non-invasive way. Vascular reactivity studies look for responses in the vessel walls to vasoactive substances or physiological paradigms that elicit an endogenous vasoactive response. It is believed that these functional changes at the microvascular level take place much earlier than the development of hypertension and if detected early enough, may be reversed with novel therapeutic approaches. In this proposal, we will perform experiments that will validate our hypothesis in several forms of hypertension in previously well established animal models and then extend them to human kidneys. Animal models will allow for direct comparison of BOLD MRI measurements against invasive laser probe assessments. Our human studies are designed to test the hypothesis that subjects at risk for developing hypertension will exhibit reduced renal microvascular reactivity. Successful outcome will provide better understanding of pathophysiology of human hypertension. PERFORMANCESITE(S) (organization,city,state) Evanston Northwestern Healthcare, Evanston, IL KEYPERSONNEL.Seeinstructions. Usecontinuationpagesas neededto providethe requiredinformationinthe formatshownbelow. Startwith PrincipalInvestigator.List all otherkey personnelin alphabeticalorder,last namefirst. Name Organization Role onProject Pottumarthi V. Prasad, Ph.D. Evanston Northwestern Healthcare Principal Investigator Luping Li, Ph.D. Evanston Northwestern Healthcare Sr. Research Associate Pippa Storey, Ph.D. Evanston Northwestern Healthcare Collaborator TBA Evanston Northwestern Healthcare Research Assistant Sean Tutton, M.D. Evanston Northwestern Healthcare Collaborator Linda Pierchala, R.N. Evanston Northwestern Healthcare Research Coordinator Laura Fogelson Evanston Northwestern Healthcare Veterinary Technician Daniel Batlle, M.D. Feinberg School of Medicine at Consultant Northwestern University Allen Cowley Jr, Ph.D. Medical College of Wisconsin Consultant Ai-ping Zou, M.D., Ph.D. Medical College of Wisconsin Consultant David Basile, Ph.D. Medical College of Wisconsin Consultant Franklin H. Epstein, M.D. Beth Israel Deaconess Medical Center Consultant Disclosure Permission Statement. Applicableto SBIR/STTROnly. Seeinstructions. [] Yes [] No o PHS 398(Rev.05/01) Page_2 Form Page2 o n Principal InvestigatodProgram Director (Last, first, middle): Prasad, Pottumarthi Fara, Ph.D. Disclosure Permission Statement. Applicable to SBIPJSTTR Only. See instructions. [] Yes [] No The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,