Download Herman B Wells Center for Pediatric Research

Wells Center for Pediatric Research
Pediatric Diabetes Research Group
Department of Pediatrics
Indiana University School of Medicine
www.wellscenter.iupui.edu
Research Interests
The Pediatric Diabetes Research Team is committed to understanding the biology
and molecular mechanisms that lead to the development of both type 1 and type 2
diabetes in children. Currently, our research team has 4 nationally recognized NIH
-funded principal investigators whose research focuses on the development, function, and survival of insulin producing pancreatic islets. These investigators are
supported by an outstanding team of researchers at multiple levels, including research faculty, postdoctoral fellows, graduate students, and undergraduates. Our
research space is in the state-of-the-art Van Nuys Medical Science Building.
Research Projects
Raghu Mirmira, MD, PhD
My laboratory is interested in the pathogenesis of both type 1 and type 2 diabetes,
but primarily from the perspective of pancreatic islet physiology. To investigate the
molecular mechanisms of islet destruction in both forms of diabetes, my laboratory
focuses on the regulation of gene transcription during pancreatic islet development,
function, and survival. The projects in my laboratory fall into three categories: 1) the
role of homeodomain transcription factors, basic helix-loop-helix transcription factors, and PPAR-gamma during the development of islets and the pathogenesis of
islet dysfunction in type 1 and type 2 diabetes, (2) the interrelationships between
chromatin structure and gene transcription in the mature islet, and (3) the role of
post-transcriptional mechanisms in cytokine-mediated islet dysfunction. We believe
that intervening at any of these three stages in the islet life-cycle will allow for the
development of new sources of islets for the treatment of diabetes.
Faculty:
Raghu Mirmira, MD, PhD,
Program Director
Debbie C. Thurmond, PhD
Associate Director
Carmella Evans-Molina, MD,
PhD
Patrick T. Fueger, PhD
Debbie C. Thurmond, PhD
Type 2 diabetes is a ‘two-hit’ disease; one ‘hit’ is dysfunction of glucose clearance by the skeletal muscle and adipose tissues
(GLUT4 vesicle translocation), and another ‘hit’ is dysfunction of insulin secretion by the pancreatic islet beta cells (insulin
granule exocytosis). Remarkably, these seemingly divergent processes require similar molecular machinery termed SNARE
proteins, and aberrant quantities and functions of particular SNARE and SNARE-associated proteins are implicated in each
‘hit’ of diabetes. Specifically, the aberrant function of the Munc18c protein with its binding partner Syntaxin 4 has been reported in diabetic human muscle and islets and therefore carries great potential for development of novel therapeutic
strategies that could simultaneously tackle both ‘hits’ of this disease to improve the livelihood of people with diabetes.
Current treatments of diabetic patients with insulin delivery or other stimulants of insulin release fail to mimic the body’s
natural and complex pattern of insulin secretion, often resulting in hypoglycemia problems and eventual beta cell failure.
Thus, another focus area of the lab is in deciphering the mechanisms used by pancreatic islet beta cells to meter insulin release, and then devise ways to recapitulate this metering mechanism pharmacologically in the patient. Thousands of insulin granules exist behind a filamentous actin (F-actin) barrier in the beta cell and F-actin remodeling is known to mobilize
To support research at the Herman B Wells Center for Pediatric Research, contact:
Riley Children’s Foundation, 30 S. Meridian St., Suite 200, Indianapolis, IN 46204-3509
317-634-4474 (877-867-4539 toll free) ● [email protected]
Wells Center for Pediatric Research
Pediatric Diabetes Research Group
Department of Pediatrics
Indiana University School of Medicine
www.wellscenter.iupui.edu
Research Projects
granules to the t-SNARE proteins at the cell surface, yet the mechanisms involved in
remodeling and granule mobilization are largely unknown and untested. We and others have made progress in discovering that a key protein in this is Cdc42, a small Rho
family GTPase that promotes actin reorganization in response to glucose. We also have
discovered that Cdc42 ‘multi-tasks’ and also functions in targeting insulin granules directly to the SNARE proteins at the cell surface. Thus, pharmacologically targeting
Cdc42 signaling in an effort to enhance actin-mediated granule mobilization may also
impact granule targeting to SNARE proteins.
Current Areas of
Research Include:
● Basic diabetes research
● Pancreatic islets
● Islet transplantation
Patrick T. Fueger, PhD
Glucose homeostasis is primarily maintained by the intricate balance of the glucoregulatory, pancreatic hormones insulin and glucagon. Type 1 diabetes mellitus results
from the autoimmune destruction of pancreatic beta cells which produce insulin. Currently, the only available cure for type 1 diabetes is pancreatic or islet transplantation.
A primary limitation of these bona fide cures is the limited availability of pancreata and
pancreatic islets from cadaver donors. Moreover, islet transplants are compromised by
the rapid decline in beta cell mass that occurs immediately following transplantation.
Because of this bottleneck in islet availability, much work has been performed with the
goal of finding an alternative source of insulin-producing cells as well as establishing
methods to stimulate proliferation of islets harvested for transplantation. The focus of
my research program addresses the critical need to establish methods to increase functional pancreatic islet mass. The projects currently being conducted in the laboratory are
directed towards identifying novel beta growth factors, elucidating their signaling pathways, and translating these discoveries into animal transplantation and/or beta cell expansion models. We are also attempting to minimize deficits in functional beta cell
mass that occur in diabetes by abrogating cell death.
● Pathophysiology of
diabetes
● Molecular pathways
● Insulin-producing cells
● Stem cell transplantation
● Targeted therapies
Events
American Diabetes Association
Carmella Evans-Molina, MD, PhD
The incidence of diabetes mellitus in our country is increasing in epidemic proportions.
The efforts in our lab are focused on three key aspects of research related to diabetes:
1. Transcriptional regulation of beta cell function: Our work in this area focuses on the
regulation of genes involved in beta cell function and the interplay between chromatin
modulation and gene expression. 2. Novel stem-cell based therapies for Type 1 diabetes: Through collaborative efforts with researchers at the Indiana Center for Vascular
Biology and Medicine, projects are underway to investigate the paracrine effects of tissue specific stem cells in preserving beta cell mass and function following islet transplantation. 3. Epigenetic mechanisms of diabetic macrovascular complications: We are
beginning projects to examine the role of Set7/9, a histone methyltransferase, in the sustained activation of NF-kB dependent inflammatory pathways in response to hyperglycemia in macrophages and endothelial cells.
Indiana Diabetes Association-Camp, Walk
To support research at the Herman B Wells Center for Pediatric Research, contact:
Riley Children’s Foundation, 30 S. Meridian St., Suite 200, Indianapolis, IN 46204-3509
317-634-4474 (877-867-4539 toll free) ● [email protected]