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Fumihiko Urano, Ph.D.,M.D.Academic Role: Associate Professor
Faculty Appointment(s) In:
Other Affiliation(s):
Rotation ProjectsYou can participate in numerous ongoing projects in our laboratory. The goal of our laboratory is to develop new clinical approaches for ER stress diseases such as diabetes, neurodegenerative diseases (e.g., ALS, Alzheimer's disease) and aging process. A. DiabetesDiabetes is a group of disorders defined by a state of high blood sugar caused by an absolute deficiency of insulin (type 1 diabetes) or a relative deficiency of insulin (type 2 diabetes). Secreted from pancreatic beta cells, insulin is essential to lowering blood sugar. While patients with type 2 diabetes need to take medications that stimulate insulin secretion from beta cells, patients with type 1 diabetes lack insulin-producing beta cells and need to inject themselves with synthetic insulin. Our data strongly suggest that ER stress-mediated beta-cell dysfunction and beta-cell death have important functions in the pathogenesis of both type 1 and type 2 diabetes. Project 1. To define the role of IRE1 signaling in pancreatic beta cells. IRE1 is an enzyme localized to the endoplasmic reticulum and a central component of the unfolded protein response (UPR) that counteracts ER stress. Our results demonstrate an important relationship between the biosynthesis of insulin and the activation of IRE1 signaling in pancreatic beta cells. We will define the function of IRE1 signaling in pancreatic beta cells using tissue culture system and mouse model. We will also develop a system to control IRE1 signaling in pancreatic beta cells using a conditionally active form of IRE1. Project 2. To study the molecular mechanisms of beta cell death mediated by ER stress. Our preliminary results suggest that only a slight increase in ER stress could lead to beta cell death. Using tissue culture system and mouse model, we will test if beta cells become more resistant to ER stress when we reduce the baseline level of ER stress by manipulating insulin biosynthesis. Project 3. To determine if synthetic peptide-based activators of IRE1 make beta cells more resistant to ER stress-mediated cell death. Our preliminary data indicate that a synthetic peptide, glucagon-like peptide 1 (GLP-1) fragment 7-37, is an activator of IRE1. Using mouse primary islets and beta-cell lines, we will test if the treatment of beta cells with GLP-1 fragment 7-37 makes beat cells more resistant to ER stress. We will also study the function of GLP-1 analog, Exendin-4, in IRE1 activation and resistance to ER stress. Project 4. To determine whether downstream components of IRE1, WFS1 and WIND, have important functions in protecting beta cells from ER stress-mediated cell death. We have found that WFS1 and WIND, which are downstream components of IRE1 in pancreatic beta cells, protect beta cells from ER stress-mediated apoptosis. We will study the expression levels of WFS1 and WIND in beta cell lines and mouse primary islets treated with GLP-1 and Exendin-4. We will also study the viability of WFS1-knockdown and WIND-knockdown beta cells under ER stress conditions. Project 5. To screen chemical compounds that activate IRE1. We will screen additional drugs that can ideally be taken orally for the activation of IRE1.B. Wolfram syndrome-Diabetes and NeurodegenerationPatients with Wolfram syndrome, a genetic disorder, develop diabetes mellitus, as well as neurodegenerative disorders such as optic atrophy, diabetes insipidus, and auditory nerve deafness. Families that exhibit Wolfram syndrome share mutations in a gene encoding WFS1 protein, a transmembrane protein localized to the endoplasmic reticulum (ER). This, at present, is the only clue to the pathogenesis of Wolfram syndrome. We and other groups have recently discovered that WFS1 has an important function in mitigating ER stress in pancreatic beta cells. Therefore, loss of function of WFS1 causes a high level of ER stress that leads to beta-cell dysfunction and death. Project 6. To determine the physiological mechanisms whereby WFS1 lowers ER stress levels in pancreatic beta cells. We hypothesize that WFS1 negatively regulates ER stress by protein degradation and mitigates ER stress in beta cells. We will determine the physiological mechanisms whereby WFS1 mitigates ER stress levels in pancreatic beta cells and neurons. Project 7. To determine whether WIND protects pancreatic beta cells from apoptosis in Wolfram syndrome. We hypothesize that WIND, a novel anti-apoptotic factor in ER stress signaling, functions in preventing ER stress-induced beta-cell death and neuronal cell death. We will study the anti-apoptotic function of WIND in beta cells and neurons.
Office: LRB - 522
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55 Lake Avenue North Worcester, MA 01655