This three-year training plan is a research-intensive and comprehensive proposal tailored to a postdoctoral fellow, Dr. S. Colvin, according to her future career goals. The focused study on islet biology and the immunology of diabetes, as well as the acquisition of new skills such as the culturing of mouse and human islets, islet isolation, and flow cytometry will promote the growth and development of Dr. Colvin?s professional career. Dr. Mirmira?s laboratory facilities, collaborations, and commitment to excellent mentoring will contribute to the successful completion of the proposed project as well as to Dr. Colvin?s overall career development. Dr. Colvin?s proposed participation in career development workshops, the Preparing Future Faculty program, departmental seminars, lab meetings, journal club, regional and national meetings, and the collaborative research environment at Indiana University will provide a comprehensive training and career development experience that will position Dr. Colvin for a career as an independent academic researcher. The research aspect of this proposal will focus on the role of the enzyme deoxyhypusine synthase (DHS) in type 1 diabetes mellitus (T1DM) pathogenesis. The development of T1DM involves a complex cascade of events that occurs between cells of the immune system (antigen-presenting cells, CD4+ and CD8+ T cells, macrophages, and B cells) and the Beta cells of the pancreas, leading to the release of pro-inflammatory cytokines and pro-death signals that cause the demise of the Beta cells. Recent studies from our laboratory have shown that the normal response to cytokine stress within the Beta cell is dependent on a posttranslationally modified form of eukaryotic translation initiation factor 5A (eIF5A), called hypusinated eIF5A (eIF5A[Hyp]). The enzyme responsible for the hypusination of eIF5A is DHS, whose specificity is exclusive for eIF5A. The proposed research plan will utilize small molecule inhibition, RNA interference, and mouse knockout reagents to investigate the role of DHS in Beta cell destruction in the setting of T1DM.
Two aims are propsed:
Aim 1 : Determine the role of DHS in the pathogenesis of T1DM in vivo in NOD mice.
Aim 2 : Determine the role of DHS specifically within mouse and human islets, in the pathogenesis of Beta cell destruction in T1DM. Together, the two aims will provide an excellent research training mechanism and will contribute to a fundamental understanding of the nature of signals that promote disease pathogenesis in T1DM.
Beta cell development, function, and regeneration are crucial avenues to research in pursuit of the goal of restoring Beta cell mass to individuals with type 1 diabetes;however, in order for these strategies to be successfully translated to human disease, the toxic environment of autoimmunity and inflammation that destroyed the original Beta cells has to be addressed. This research proposal further investigates a novel pathway that regulates the inflammatory stress response of islets in Type 1 diabetes, and may identify a novel target for the prevention of this disease.
|Maganti, Aarthi V; Tersey, Sarah A; Syed, Farooq et al. (2016) Peroxisome Proliferator-activated Receptor-Î³ Activation Augments the Î²-Cell Unfolded Protein Response and Rescues Early Glycemic Deterioration and Î² Cell Death in Non-obese Diabetic Mice. J Biol Chem 291:22524-22533|
|Prince, Kelly L; Colvin, Stephanie C; Park, Soyoung et al. (2013) Developmental analysis and influence of genetic background on the Lhx3 W227ter mouse model of combined pituitary hormone deficiency disease. Endocrinology 154:738-48|
|Cabrera, S M; Colvin, S C; Tersey, S A et al. (2013) Effects of combination therapy with dipeptidyl peptidase-IV and histone deacetylase inhibitors in the non-obese diabetic mouse model of type 1 diabetes. Clin Exp Immunol 172:375-82|
|Colvin, Stephanie C; Maier, Bernhard; Morris, David L et al. (2013) Deoxyhypusine synthase promotes differentiation and proliferation of T helper type 1 (Th1) cells in autoimmune diabetes. J Biol Chem 288:36226-35|
|Tersey, Sarah A; Nishiki, Yurika; Templin, Andrew T et al. (2012) Islet Ã½Ã½-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. Diabetes 61:818-27|
|Dong, Yuanshu; Zhang, Lujuan; Zhang, Sheng et al. (2012) Phosphatase of regenerating liver 2 (PRL2) is essential for placental development by down-regulating PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) and activating Akt protein. J Biol Chem 287:32172-9|