Emerging physiologic and genetic data suggest that dysfunction of the pancreatic beta cell is the key determinant of whether an insulin resistant individual will progress to frank hyperglycemia and diabetes. The long-range goal of this applicant is to define the pathways that govern beta cell function and survival in states of health in order to understand how these regulatory circuits are impaired in the pathologic state of Type 2 diabetes mellitus. The sarco-endoplasmic reticulum calcium ATPase or SERCA pump resides in the endoplasmic reticulum membrane and is responsible for maintaining a steep calcium concentration gradient between the cytosol and endoplasmic reticulum. In the beta cell, this gradient plays a key role in regulated insulin secretion and the maintenance of endoplasmic reticulum health and function. Preliminary and published work has revealed that expression of the predominant beta cell isoform, SERCA2, is markedly downregulated in rodent and human models of Type 2 diabetes mellitus. Furthermore, loss of SERCA2 expression leads to profound changes in beta cell secretory function and intracellular calcium flux in response to glucose. Given this background, the overall hypothesis of this proposal is that dysregulation of SERCA2 activity and expression is a key contributor to the beta cell dysfunction and death observed in Type 2 diabetes mellitus. To test this hypothesis, three aims are proposed.
Aim 1 : elucidate the in vivo role of SERCA2 in beta cell function using two novel mouse models of SERCA2 deficiency.
Aim 2 : delineate the transcriptional pathways that regulate SERCA2 expression in the pancreatic beta cell under normal conditions and in diabetes.
Aim 3 : elucidate the contribution of microRNAs in disruption of the SERCA2 gene regulatory network. The successful completion of these aims will precisely define the role of islet beta cell SERCA2 in metabolic and glucose homeostasis and identify the pathways that lead to its transcriptional dysregulation in Type 2 diabetes mellitus.

Public Health Relevance

Type 2 diabetes mellitus affects nearly 1 in 12 Americans and is a leading cause of blindness, kidney failure, amputations, and heart disease. Dysfunction of the insulin producing beta cells in the pancreas plays a prominent role in the development of diabetes. The goal of this project is to define the molecular pathways that lead to beta cell failure in Type 2 diabetes in order to inform the development of novel and improved therapeutic strategies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK093954-04
Application #
8724486
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Johnson, Justin S; Evans-Molina, Carmella (2015) Translational implications of the ?-cell epigenome in diabetes mellitus. Transl Res 165:91-101
Blue, Emily K; Ballman, Kimberly; Boyle, Frances et al. (2015) Fetal hyperglycemia and a high-fat diet contribute to aberrant glucose tolerance and hematopoiesis in adult rats. Pediatr Res 77:316-25
Maganti, Aarthi; Evans-Molina, Carmella; Mirmira, Raghavendra G (2014) From immunobiology to *-cell biology: The changing perspective on type 1 diabetes. Islets 6:
Mirmira, Priyadarshini; Evans-Molina, Carmella (2014) Bisphenol A, obesity, and type 2 diabetes mellitus: genuine concern or unnecessary preoccupation? Transl Res 164:13-21
Mastracci, Teresa L; Evans-Molina, Carmella (2014) Pancreatic and Islet Development and Function: The Role of Thyroid Hormone. J Endocrinol Diabetes Obes 2:
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
Rajashekhar, Gangaraju; Ramadan, Ahmed; Abburi, Chandrika et al. (2014) Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy. PLoS One 9:e84671
Erdel, Blake L; Juneja, Rattan; Evans-Molina, Carmella (2014) A case of calciphylaxis in a patient with hypoparathyroidism and normal renal function. Endocr Pract 20:e102-5
Handa, Rajash K; Evan, Andrew P; Connors, Bret A et al. (2014) Shock wave lithotripsy targeting of the kidney and pancreas does not increase the severity of metabolic syndrome in a porcine model. J Urol 192:1257-65
Kono, Tatsuyoshi M; Sims, Emily K; Moss, Dan R et al. (2014) Human adipose-derived stromal/stem cells protect against STZ-induced hyperglycemia: analysis of hASC-derived paracrine effectors. Stem Cells 32:1831-42

Showing the most recent 10 out of 18 publications