Diabetes mellitus is characterized by impaired glucose homeostasis resulting from insufficiency or functional failure of insulin-producing ??cells, alone or in association with insulin resistance. Therefore, restoring ?-cell mass and function is essential to reverse the development of diabetes. Utilizing small molecule inducers of ?-cell proliferation is a particularly promising strategy with numerous valuable features such as their oral bioavailability and target specificity. However, the slow rate of ?-cell proliferation in adult humans is a major hurdle to overcome to use this approach. Through a chemical genetic screen for small molecule enhancers of ?-cell regeneration in zebrafish, we identified several TBK1/IKK? inhibitors (TBK1/IKK?-Is). TBK1/IKK?-Is promoted ?-cell regeneration by markedly increasing proliferation of ?-cells. Mammalian target of rapamycin (mTOR) inhibitor rapamycin eliminated the effect of TBK1/IKK?-Is on regenerating ?-cells, whereas TBK1/IKK?-Is augmented mTOR activity. Interestingly, treatment with TBK1/IKK?-Is led to pronounced increase in cAMP levels. The proliferation effect of TBK1/IKK?-Is was verified in primary mammalian islets including human islets. The goal of this application is to delineate the mechanisms and the strategies of how to increase functional ?-cell mass with suppression of TBK1/IKK?. First, we will design and investigate the potency of novel TBK1/IKK?-Is on ?-cell regeneration. Using (E)-3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (abbreviated as PIAA), which markedly increases ?-cell regeneration, as a lead compound, we will perform structure-activity relationship (SAR) analyses of TBK1/IKK?-PIAA interaction. Furthermore, we will use the PIAA as a scaffold to design new molecular architectures that exhibit potent and selective TBK1/IKK? inhibition activities with minimum toxicity on ?-cell regeneration. Second, we will elucidate underlying mechanisms of TBK1/IKK?-mediated ?-cell regeneration. Given that rapamycin treatment abolished the effect of TBK1/IKK? suppression on ?-cell regeneration and TBK1/IKK?-Is enhanced mTOR activity and cAMP levels, we will test whether TBK1/IKK? suppression promotes ?-cell regeneration via modulating the cAMP-mTOR signaling cascade. We will perform biochemical and functional analyses to characterize the TBK1/IKK?-cAMP-mTOR interplay on ?-cell regeneration in vitro and in vivo. Third, we will investigate the efficacy of TBK1/IKK?-Is on expanding functional ?-cell mass in mammalian systems. We will use primary pancreatic islets to examine the potency of PIAA and its newly synthesized analogs on ?-cell replication. Furthermore, we will evaluate the ability of PIAA and its analogs to promote ?-cell expansion and enhance glycemic control in mice including a mouse model of streptozotocin (STZ)-induced diabetes.

Public Health Relevance

We will delineate the mechanisms and the strategies of how to augment functional ?-cell mass by repressing TBK1/IKK? function. The outcomes of the proposed study will make a significant breakthrough to prevail over the current bottleneck of enhancing human ?-cell proliferation in treating diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56DK111630-01A1
Application #
9539010
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2017-09-01
Project End
2017-09-02
Budget Start
2017-09-01
Budget End
2017-09-02
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Georgia Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30318
Xu, Jin; Jia, Yun-Fang; Tapadar, Subhasish et al. (2018) Inhibition of TBK1/IKK? Promotes Regeneration of Pancreatic ?-cells. Sci Rep 8:15587