Fumihiko Urano MD, PhD
|Institution||University of Massachusetts Medical School|
|Department||Program in Molecular Medicine|
|Address||Washington University School of Medicine|
660 South Euclid, Campus Box 8127
St. Louis MO 63110
|Institution||UMMS - Graduate School of Biomedical Sciences|
|Department||Interdisciplinary Graduate Program|
|Institution||UMMS - Graduate School of Biomedical Sciences|
|Institution||UMMS - Programs, Centers and Institutes|
|Department||Program in Gene Function and Expression|
Fumihiko Urano received his M.D. in 1994 and his Ph.D. in Pathology in 1998 from Keio University Graduate School of Medicine in Tokyo, Japan. In 1995, he completed his residency in Pathology at Keio University Hospital in Tokyo. From 1998 to 2002, he was a post-doctoral fellow at the Skirball Institute of Biomolecular Medicine at the New York University School of Medicine, where his work was supported by research fellowships from the Japan Society for the Promotion of Science and the Uehara Memorial Foundation. Dr. Urano joined the Program in Gene Function and Expression at the University of Massachusetts Medical School as an Assistant Professor in the fall of 2002.
Role of ER Stress in Diabetes and Aging
The goal of our laboratory is to understand the molecular mechanisms of Endoplasmic Retiuculm stress (ER stress) diseases such as Alzheimer's disease, Parkinson's disease, Prion disease, ALS and diabetes mellitus. These most devastating human diseases are associated with pathological accumulations of abnormal proteins in cells. An overwhelming body of evidence suggests that a special type of cell stress called Endoplasmic Reticulum stress (ER stress) has an important function in the pathogenesis of such diseases. We are also studying the relationship between ER stress and Aging because accumulations of abnormal proteins may accelerate age-related cellular dysfunction.
What is Endoplasmic Reticulum (ER)?
Proteins are needed for the body to function properly. They are the basis of body structures and are used to synthesize enzymes and antibodies in cells. Proteins are synthesized in our cells. However, newly synthesized proteins are not functional yet. To be functional, they should mature inside of a cellular compartment called the Endoplasmic Reticulum (ER). It is like that a baby is growing in the uterus. In the lumen of the ER, proteins obtain their proper three-dimensional structure and mature to carry out their functions (i.e., become functional). This process is called protein folding. ER has an essential function in this process, especially for secreted protein and receptors such as insulin, amyloid beta and serotonin transporter. Defects of these proteins have been known to cause diabetes, Alzheimer's disease, and bipolar disorder respectively.
What are "Endoplasmic Reticulum Stress (ER stress) Diseases"?
Protein folding in the ER is crucial for us. However, in some instances, the sensitive environment in the ER can be perturbed by pathophysiological processes such as viral infections, environmental toxins, and mutant protein expression, as well as natural processes such as the large biosynthetic load placed on the ER. This causes the accumulation of immature and abnormal proteins in cells, leading to ER stress. Our body has an adaptive response that counteracts ER stress termed "Unfolded Protein Response (UPR)". Therefore, as long as the UPR can mitigate ER stress, our body functions properly.
However, under some pathological circumstances, a lot of abnormal proteins accumulate, leading to a high level of ER stress. This high level of ER stress cannot be mitigated by an adaptive response (i.e., the UPR), leading to malfunction of our cells. These pathological circumstances include environmental stress, virus infection, genetic defects, and obesity. We group the human diseases that are associated with the accumulation of abnormal proteins in the ER into "ER Stress Diseases".
ER stress and Diabetes
Diabetes 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. We have found that a high level of ER stress has an important function in the pathogenesis of both tyep 1 and type 2 diabetes. We seek to develop new clinical approaches based on the prevention of diabetes by the development of drugs that block the ER stress-mediated cellular dysfunction.
Figure 1: Three types of adaptive responses to the accumulations of unfolded proteins in the ER.
The ER senses the folding status of newly synthesized proteins. Three types of adaptive responses are activated in response to the accumulation of unfolded proteins.
Figure 2: Schematic representation of the role of ER stress in the pathogenesis of diabetes.
Sonya Fonseca, Graduate Student
Rajarshi Ghosh, Graduate Student
Shinsuke Ishigaki, Postdoctoral Fellow
Kathryn Lipson, Postdoctoral Fellow
Christine Oslowski, Graduate Student
Karen Sargent, Research Assistant
Lee Yuan, Graduate Student
Rachel Buglione-Corbett, MD/PhD Student
Apoorva Trivedi, Intern
You 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.
Diabetes 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 Neurodegeneration
Patients 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.
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