Traditional immunomodulatory drug treatments in Type 1 Diabetes Mellitus (T1DM) have met with disappointing results, largely due to massive loss of ? cell mass by the time of clinical presentation. In combination with a rapidly increasin incidence of T1DM, these setbacks have identified a critical need for alternative treatment approaches focused on earlier identification of T1DM, at a time prior to the widespread destruction of pancreatic ? cells. Recent data suggest the intrinsic ? cell response to inflammatory and metabolic stress ultimately impacts ? survival. Aberrant microRNA (miRNA) expression has been demonstrated in the ? cell and serum in diabetes, suggesting that miRNAs may contribute to T1DM progression. The long-term goal of this applicant is establish an independent translational research career exploring the role of microRNAs in diabetes pathophysiology and to use changes in circulating levels of ? cell derived microRNAs as the basis for biomarkers that successfully identify the onset of T1DM in prediabetic individuals. This applicant's central hypothesis is that miRNA 21 (miR-21) expression is increased by the ? cell as a protective mechanism to limit ? cell death in T1DM and differences in serum miR-21 levels will signal the onset of ? cell stress in developing T1DM, thereby allowing for earlier disease detection. Three specific aims are proposed to test this hypothesis. Aim 1 will define downstream effects of miR-21 expression within the ? cell using in-vitro models of T1DM in ? cell line and mouse and human islets. Aim 2 will define the effects of ? cell specific miR-21 deletion in a mouse model of T1DM. Aim 3 will use mouse and human serum to identify miR-21 as a biomarker for T1DM. Completion of these aims will establish miR-21's role as a therapeutic modality and novel biomarker of T1DM. This K08 Mentored Clinical Scientist Research Career Development Award entails a 5-year training plan designed to achieve 4 main objectives: 1) gain expertise in state-of-the art techniques and concepts in diabetes research, 2) gain experience translating basic findings to translational studies, 3) gain expertise in oral and writtn presentation of research findings, including grant and manuscript preparation, and 4) develop professional skills necessary for an independent academic career. The applicant will benefit from the outstanding and collaborative research environment provided by the Herman B Wells Center Pediatric Diabetes Center at Indiana University School of Medicine. Her training will also benefit from a mentoring and advisory committee consisting of a diverse team of carefully selected and established NIH- funded investigators. Completion of the proposed plan will provide training and preliminary data to support an R01 application and allow the applicant to establish a career as an independent researcher using molecular discovery to address clinically relevant problems.