Our overall goal is to understand how insulin-producing ?-cells are generated and to apply that knowledge to the production of ?-cells for patients with Diabetes. Our general approach in this application is to use human islets and human embryonic stem cells to model human ?-cell genesis and turn over. We will continue to use animal models to determine how ?-cell expansion technologies work in vivo -- how they interact with the immune system and impact metabolism -- in order to develop these ideas into practical and safe human therapies.
Our Specific Aims explore three approaches to ?-cell genesis: neogenesis, proliferation, and reprogramming/transdifferentiation:
Specific Aim 1 : Translate results of regeneration screens to human ?-cells. Using zebrafish, we have identified small molecules that enhance ?-cell regeneration. We will validate these hits in human Islets and ES cells, explore their mechanisms of action, and test their activity in preclinical animal models.
Specific Aim 2 : Determine the efficacy of GPCR signaling in ?-cell genesis. We have established that GPCR signaling plays a critical role in two physiologic settings of ?-cell expansion: pregnancy and infancy. We will test the importance of these pathways in the neogenesis and turnover of human ?-cells.
Specific Aim 3 : Establish the role of the immune system in islet regeneration. Current models of islet regeneration all cause pancreatic damage and provoke an immune response. We will determine the role of these responses in islet regeneration and reprogramming in preparation for moving these technologies to human therapy.
Specific Aim 4 : Monitor and control ER stress during ?-cell genesis. We have developed technologies for monitoring and controlling the unfolded protein response (UPR) in living cells. We will utilize these technologies to determine the role of ER stress and the UPR during ?-cell genesis in human ES cells and live mice.

Public Health Relevance

These studies are directed towards the application of basic knowledge of the mechanisms by which the insulin producing cells in the pancreas are generated to the clinical problem of how to produce more of these cells for patients with Diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK089541-04
Application #
8522196
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M3))
Program Officer
Sato, Sheryl M
Project Start
2010-09-15
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$1,255,443
Indirect Cost
$340,912
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Zhu, Saiyong; Russ, Holger A; Wang, Xiaojing et al. (2016) Human pancreatic beta-like cells converted from fibroblasts. Nat Commun 7:10080
Zimmerman, Christopher A; Lin, Yen-Chu; Leib, David E et al. (2016) Thirst neurons anticipate the homeostatic consequences of eating and drinking. Nature 537:680-684
Gut, Philipp; Stainier, Didier Y R (2015) Whole-organism screening for modulators of fasting metabolism using transgenic zebrafish. Methods Mol Biol 1263:157-65
Chen, Yiming; Lin, Yen-Chu; Kuo, Tzu-Wei et al. (2015) Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160:829-41
Kim, Kyuho; Oh, Chang-Myung; Ohara-Imaizumi, Mica et al. (2015) Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state. Endocrinology 156:444-52
Huskey, Noelle E; Guo, Tingxia; Evason, Kimberley J et al. (2015) CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation. Stem Cell Reports 4:374-89
Berger, Miles; Scheel, David W; Macias, Hector et al. (2015) Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion. Proc Natl Acad Sci U S A 112:2888-93
Leib, David E; Knight, Zachary A (2015) Re-examination of Dietary Amino Acid Sensing Reveals a GCN2-Independent Mechanism. Cell Rep 13:1081-9
Maly, Dustin J; Papa, Feroz R (2014) Druggable sensors of the unfolded protein response. Nat Chem Biol 10:892-901
Tsuji, Naoki; Ninov, Nikolay; Delawary, Mina et al. (2014) Whole organism high content screening identifies stimulators of pancreatic beta-cell proliferation. PLoS One 9:e104112

Showing the most recent 10 out of 20 publications