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.

Public Health Relevance

An alarming increase in the prevalence of Type 1 Diabetes Mellitus (T1DM) combined with disappointing results of clinical trials utilizing traditional immunomodulatory therapies has highlighted a critical need for an improved understanding of the molecular etiology of T1DM. The goal of this project is to define the role of cell microRNA 21 during the progression of T1DM and to address the hypothesis that changes in circulating microRNA 21 may serve as a potential T1DM biomarker. This work will address a critical gap in our understanding of T1DM pathophysiology and has the potential to inform novel therapeutic and diagnostic strategies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZDK1)
Program Officer
Spain, Lisa M
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Sims, Emily K; Park, Grace; Mather, Kieren J et al. (2018) Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function. PLoS One 13:e0197080
Sims, Emily K; Evans-Molina, Carmella; Tersey, Sarah A et al. (2018) Biomarkers of islet beta cell stress and death in type 1 diabetes. Diabetologia 61:2259-2265
Lakhter, Alexander J; Pratt, Rachel E; Moore, Rachel E et al. (2018) Beta cell extracellular vesicle miR-21-5p cargo is increased in response to inflammatory cytokines and serves as a biomarker of type 1 diabetes. Diabetologia 61:1124-1134
Sims, Emily K; Lakhter, Alexander J; Anderson-Baucum, Emily et al. (2017) MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells. Diabetologia 60:1057-1065
Sims, Emily K; Chaudhry, Zunaira; Watkins, Renecia et al. (2016) Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes. Diabetes Care 39:1519-26
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Lakhter, Alexander J; Sims, Emily K (2015) Minireview: Emerging Roles for Extracellular Vesicles in Diabetes and Related Metabolic Disorders. Mol Endocrinol 29:1535-48
Hatanaka, Masayuki; Maier, Bernhard; Sims, Emily K et al. (2014) Palmitate induces mRNA translation and increases ER protein load in islet ?-cells via activation of the mammalian target of rapamycin pathway. Diabetes 63:3404-15