BB Principal Investigator/Program Director (Last, first, middle): Ray, Patricio E. DESCRIV]'ION: State the application's broad, long-term objectives and specific aims, making referen,oe to the health, relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This description is meant to serve as a sucdnctaccurate description of the proposed work when separated flora the appfication. If the application is fimded, this description, as is, will become mblic infonnation. Therefore,donot include proprietary/confidential information. DO NOT F.,XCEEDTHE SPACE PROVIDED. The Hemolytic Uremic Syndrome (HUS) is an important cause of acute renal failure in children. In the first period of the grant, we have shown that HIV-infected children can develop an atypical clinical form of HUS characterized by a significant renal angiogenic-fibrogenic response, rapid progression of the renal disease, and high mortality. We found elevated urine concentrations of the angiogenic growth factors, bFGF, HIV-Tat protein, and a Fibroblast Growth Factor binding protein (BP-FGF), in children with HIV-HUS. Very little is known about the role that these angiogenic factors and HIV-1 play in the pathogenesis of childhood HIV-HUS. We hypothesize that HIV-1 causes renal glomemla~ endothelial (RGEc) and tubular epithelial cel! (RTEc) injury and induces an an~ogenic, pro-coagulant renal O/tokine miljen that accelerates the progression of the renal disease in children with HIV-HU$. To test this hypothesis we will:/) Determine the basic mechanisms by which HIV-I induces renal injury m the context ofHIV-HUS, and define how ang~ogenicfactors accumulated in the/gdney modulate the cytopathic effectsofHIV-1. The specific pathogenic roles of HIV-1 isolates and plasma samples fi,om children with or without HIV-HUS, HIV-HELPP (an incomplete form of HIV- HUS), HIV-1 proteins and co-receptors, the glycolipid Gb3, and FGF's/Tat, will be determined in cultured human RGEc and urinary RTEc isolated fi'om children with HIV-HUS, using fusion, attachment, and cytopathic assays 2) Define how HIV-1 and Tat modulate the synthesis and release ofBP-FGF in PBMC% and the mitogenic-fibrinolyticactivity ofBP- FGF/FGF's in cultured human RGEc. We will define a novel mechanism by which HIV-1 could modulate the activity of FGF's in peripheral blood mononuclear cells (PBMC's) and RGEc, mainly by regulating the synthesis, release, and/or the mitogenic-fibrinolytic activity of BP-FGF. 3) Explore the in vivorole ofHIV-1 and Tat in HIV-HUS, using young rats carrying a deletion gag-poi mutant of the hybrid HIV-1viruspNL4-3, or infected with rAd vectors carrying the human CD4 antigen or Tat m renal glomerular cells. An HIV-HUS-like syndrome, similar to that seen in children with HIV-HUS, will be induced by injecting the toxin ricin (which mimics a Shiga toxin) in HIV-Tg rats. These studies will determine whether the presence of HIV-1/Tat in the kidney, increases the accumulation of renal angiogenic factors and fibrin, and accelerates the progression of the tubulointerstitial lesions in comparison to control rats, and define whether HIV-1 can cause a cytopathic infection in rat RGEc expressing CD4 and induce an HUS-like syndrome. These studies should generate new fundamental knowledge to define the role of HIV-1 in the pathogenesis of childhood HIV-HUS and other AIDS related angiogenic clinical conditions, and generate a small animal model system of HIV-HUS. PERFORMANCE SITE ========================================Section End===========================================
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