Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK089541-03
Application #
8322756
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
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$1,301,497
Indirect Cost
$459,104

  Institution

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

  Publications

Krentz, Nicole A J; van Hoof, Dennis; Li, Zhongmei et al. (2017) Phosphorylation of NEUROG3 Links Endocrine Differentiation to the Cell Cycle in Pancreatic Progenitors. Dev Cell 41:129-142.e6
Zhu, Saiyong; Russ, Holger A; Wang, Xiaojing et al. (2016) Human pancreatic beta-like cells converted from fibroblasts. Nat Commun 7:10080
Russ, Holger A; Landsman, Limor; Moss, Christopher L et al. (2016) Dynamic Proteomic Analysis of Pancreatic Mesenchyme Reveals Novel Factors That Enhance Human Embryonic Stem Cell to Pancreatic Cell Differentiation. Stem Cells Int 2016:6183562
Baeyens, L; Hindi, S; Sorenson, R L et al. (2016) ?-Cell adaptation in pregnancy. Diabetes Obes Metab 18 Suppl 1:63-70
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
Leib, David E; Knight, Zachary A (2015) Re-examination of Dietary Amino Acid Sensing Reveals a GCN2-Independent Mechanism. Cell Rep 13:1081-1089
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
Gut, Philipp; Stainier, Didier Y R (2015) Whole-organism screening for modulators of fasting metabolism using transgenic zebrafish. Methods Mol Biol 1263:157-65
Berger, Miles; Scheel, David W; Macias, Hector et al. (2015) G?i/o-coupled receptor signaling restricts pancreatic ?-cell expansion. Proc Natl Acad Sci U S A 112:2888-93
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

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