[unreadable] The goal of this program is to develop and ultimately commercialize small molecule drugs that induce (-cell replication and/or differentiation for the treatment and potential cure of type 1 diabetes (T1D). Molecules that induce (-cell regeneration will be identified using high-throughput, high-content screens of small molecule compounds that act on the two major pathways by which (-cell regeneration occurs: replication of preexisting (-cells and neogenesis from endocrine progenitors within the pancreas. The first screen will identify compounds that upregulate insulin promoter activity. These compounds may be useful for inducing (-cell differentiation from precursors, either in vitro (e.g., from ES cells) to increase the supply of (-cells for transplantation or in vivo from adult progenitors. The second screen will identify compounds that repress p57Kip2 activity. These compounds may be useful for inducing (-cell replication either in vitro to increase the supply of islets for transplantation or possibly in vivo for inducing replication of the patients remaining (-cells. [unreadable] The insulin and p57Kip2 assays will be used to screen a 50,000 compound diversity library designed with bias towards "drug-like" properties and customized sub-libraries. Hits from initial screens will be confirmed in a panel of functionally relevant assays. Compounds that pass primary and confirmatory will be selected from both the insulin and p57kip2 assays. The goal is to identify appropriate core structures for the development of 1-3 lead series of compounds to develop Structure-Activity-Relationships (SAR) based on assay results. We anticipate synthesizing at least 25 compounds per series to explore SAR. From these compounds, 3-10 lead candidates will be selected for Phase II PK/ADMET and pre-clinical animal studies. [unreadable] The specific aims for this project are: 1) select and acquire a 50,000 compound screening library and design smaller focused libraries based on initial screening results, 2) identify, confirm, and characterize small molecule compounds that up-regulate insulin expression ((-cell differentiation) in a high throughput screen using a human (-cell model, 3) develop a high throughput screen for p57Kip2 expression ((-cell replication) in a human (-cell model, 4) identify, confirm, and characterize small molecule compounds that down-regulate p57Kip2 expression in a human (-cell model, and 5) develop SAR of lead molecules (1-3 lead series) and select 3-10 candidates for optimization in Phase II. [unreadable] The only approach that has been shown to establish and maintain normoglycemia in patients with T1D is replacement of the non-functioning (-cells via pancreas, islet, or (-cell transplant; but these are severely limited due to the shortage of donor pancreases. This proposal is focused on developing compounds that in the short term would dramatically increase the number of insulin-producing cells available for transplant and in the longer term might allow the re-establishment of the patient's own (-cells. [unreadable] [unreadable]