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.
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.
|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|
|Baeyens, L; Hindi, S; Sorenson, R L et al. (2016) ?-Cell adaptation in pregnancy. Diabetes Obes Metab 18 Suppl 1:63-70|
|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|
|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|
|Chen, Yiming; Lin, Yen-Chu; Kuo, Tzu-Wei et al. (2015) Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160:829-41|
|Gut, Philipp; Stainier, Didier Y R (2015) Whole-organism screening for modulators of fasting metabolism using transgenic zebrafish. Methods Mol Biol 1263:157-65|
|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|
Showing the most recent 10 out of 23 publications