This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 0099 Primary focal segmental glomerulosclerosis (FSGS) is a serious renal disease, accounting for nearly 10-15% of all pediatric and adult patients requiring chronic dialysis or transplantation. Not only is the incidence of this disease rising. The etiology of FSGS remains obscure and there is no proven therapy. In the absence of a well-defined therapeutic target and a candidate treatment, this proposal will evaluate the safety and efficacy of three novel agents that may have the capacity to reduce renal fibrosis and slow the rate of deterioration of disease in patients with resistant FSGS. The Phased Innovation Award application is composed of two distinct portions. During the initial stage, the R21 Phase, the safety, tolerance, and pharmacokinetic profile of two novel therapies - a TNF-a (tumor necrosis factor-a) antagonist and a PPARg agonist -- will be tested. In the second stage, the R33 phase, a hybrid ranking and selection Phase II study will be performed to assess the efficacy of these two treatments and an anti-TGF-b (tumor growth factor-b)antibody compared to optimal conservative medical therapy. The outcome of this study will guide the design of a formal Phase III randomized clinical trial. The infrastructure that is established for the performance of this R21/R33 project should prove useful for the efficient assessment of additional novel therapies that will to arise in the future.