Diabetes mellitus is a group of disorders characterized by an absolute or relative deficiency of insulin produced by pancreatic ? cells. Increasing evidence now indicates that sustained endoplasmic reticulum (ER) stress plays a critical role in ? cell death in type 1 and type 2 diabetes, as well as genetic forms of diabetes including Wolfram syndrome. Targeting the ER, therefore, offers the possibility of a novel therapeutic approach to managing patients with diabetes. Despite the underlying importance of ER dysfunction and ER stress in ? cell death, there is no effective treatment for diabetes targeting the ER due to the complex etiologies of type 1 and type 2 diabetes. Our strategy for overcoming this challenge is to focus on Wolfram syndrome in which mutations in a single gene, WFS1, are involved in ER dysfunction and ? cell death. We will test the hypothesis that ER calcium stabilizers and mesencephalic astrocyte-derived neurotorophic factor (MANF) can ameliorate ER stress-mediated cell death in Wolfram syndrome, a prototype of ER stress-induced ? cell death. Our study on Wolfram syndrome may lead to novel treatments for type 1 and type 2 diabetes.

Public Health Relevance

Increasing evidence indicates that sustained endoplasmic reticulum (ER) stress plays a critical role in ? cell death in type 1 and type 2 diabetes, as well as genetic forms of diabetes including Wolfram syndrome. Targeting the ER, therefore, offers the possibility of a novel therapeutic approach to managing patients with diabetes. Despite the underlying importance of ER dysfunction and ER stress in ? cell death, there is no effective treatment for diabetes targeting the ER due to the complex etiologies of type 1 and type 2 diabetes. Our strategy for overcoming this challenge is to focus on a rare genetic disorder, Wolfram syndrome, in which mutations in a single gene, WFS1, are involved in ER dysfunction and ? cell death. We will develop novel treatments for Wolfram syndrome in this proposal. Our study on Wolfram syndrome may lead to novel treatments for type 1 aid type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK112921-02
Application #
9565574
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Wang, Xujing
Project Start
2017-09-14
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130