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Doris
A. Stoffers, MD, PhD
Associate
Professor , Depts of Medicine, Division of Endocrinology,
Metabolism and Diabetes
Genetics
and Gene Regulation Program
Address
Division of Endocrinology,
Diabetes and Metabolism
Department of Medicine
726 Clinical Research Building
415 Curie Blvd
Philadelphia, PA 19104
Office tel.: 215 573-5413
Lab tel.: 215 573-6647
Fax: 215 898-5408
E-mail: stoffers@mail.med.upenn.edu
Education
Johns
Hopkins University BA
(Chemistry)1984
Johns Hopkins Medical School, PhD (Neuroscience) 1991
Johns Hopkins Medical School, MD, 1991
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Research
Interests
- transcription factors and signal transduction
- embryonic development and adult regeneration
of the endocrine pancreas
- relationship of defects in these pathways
to the pathophysiology of diabetes mellitus, a disease caused
by a deficiency in the production or action of insulin
Key
words: Diabetes, insulin, beta
cell, pancreas development, transcriptional regulation, signal
transduction.
Description
of Research
Research in our laboratory focuses on the embryonic
development and adult regeneration of the endocrine pancreas,
and the relationship of defects in these pathways to the pathophysiology
of diabetes mellitus, a disease caused by a deficiency in
the production or action of insulin. The beta cells of the
endocrine pancreas are the only source of insulin production
in the body and dysregulation of beta cell mass is pivotal
to the development of diabetes. Thus, successful therapies
aimed at correcting diabetes will likely impact beta cell
growth and/or function. Further support for this focus derives
from genetic studies linking monogenic forms of human diabetes
to mutations in transcription factors that regulate the development
of beta cell mass. The emphasis of this laboratory on the
Pancreatic Duodenal homeoboX 1 gene (Pdx-1)
is driven by three observations: (1) Pdx1 is critically required
for the development of all pancreatic lineages, as evidenced
by pancreatic agenesis in mice and humans homozygous for null
mutations in the Pdx1 gene, (2) human heterozygous mutations
in Pdx1 cause monogenic forms of early and late onset diabetes,
and (3) Pdx1 is an essential mediator of islet compensation
in genetic mouse models of insulin resistance. We propose
that elucidating the molecular mechanisms of Pdx1 action in
the developing and adult ß cell will result in identification
of novel therapeutic targets and strategies for diabetes,
through the genetic or pharmacologic manipulation of these
targets in vivo to promote endogenous ß cell regeneration
or ex vivo to increase the supply and function of the severely
limited number of human islets available for transplantation.
Understanding these molecular mechanisms will also inform
efforts to develop alternate ß cell replacement sources,
such as through the guided differentiation of human stem cells
or the transdifferentiation of more plentiful mature cell
populations. We also strive to understand the mechanisms whereby
incretin hormones like GLP-1 improve ß cell function
and survival.
Current projects include:
- Characterization of a novel PDX-1 C-terminus
Interacting Factor, PCIF1, identified in a yeast two-hybrid
screen. PCIF1 is a nuclear factor that inhibits PDX-1 transactivation.
Biochemical, molecular, in vivo and human genetics approaches
are being applied to elucidate the role of this novel regulatory
molecule.
- Characterization of mouse models of PDX-1
insufficiency that are revealing novel roles for PDX-1 in
islet progenitor specification during embryonic development
and islet compensation for insulin resistance in adulthood.
- Identification of PDX-1 target genes using
high throughput chromatin immunoprecipitation and cDNA microarrays.
- Elucidation of biological and molecular
mechanisms by which the incretin hormone GLP-1 stimulates
expansion of beta cell mass, with a particular emphasis
on signal transduction and transcriptional target identification.
Recent
Publications
Oliver-Krasinski J and Stoffers DA. On the
Origin of the Beta Cell. Genes and Development 2008;
in press.
Desai BM, Oliver-Krasinski J, De León
DD, Farzad C, Hong N, Leach SD, Stoffers DA. Preexisting pancreatic
acinar cells contribute to acinar cell, but not islet beta
cell, regeneration. Journal of Clinical Investigation
2007;117(4):971-7.
Park JH, Stoffers DA, Nicholls, RD, Simmons
RA. Developmental Origins of Type 2 Diabetes: Progressive
Epigenetic Modifications Silence Pdx1. Journal of Clinical
Investigation, 2008, in press.
De León DD, Li C, Delson M, Matschinsky
F, Stanley CA, and Stoffers DA. Exendin-(9-39) corrects fasting
hypoglycemia in SUR1-/- mice by lowering cAMP in pancreatic
ß-cells and inhibiting insulin secretion. Journal
of Biological Chemistry 2008; in press.
De Leon DD, Farzad C, Crutchlow MF, Brestelli
J, Tobias J, Kaestner KH, Stoffers DA. Identification of transcriptional
targets during pancreatic growth after partial pancreatectomy
and exendin-4 treatment. Physiol Genomics. 2006;24(2):133-43.
Liu A, Desai BM, Stoffers DA. Identification
of PCIF1, a POZ domain protein that inhibits PDX-1 (MODY4)
transcriptional activity. Mol Cell Biol. 2004;24(10):4372-83.
Search PubMed for more articles
Lab
Rotation
Projects
Lab rotation projects are available in all of
the major areas described above. Please arrange for an appointment
to discuss.
Lab
personnel:
Doris A. Stoffers, MD, PhD, Principal Investigator
David Groff, Research Specialist
Juxiang Yang, PhD, Research Specialist
Jennifer Oliver-Krasinski, graduate student, MD-PhD candidate
(Pharmacology)
Mira Sachdeva, graduate student, MD-PhD candidate (CAMB)
Katy Claiborn, graduate student, PhD candidate (CAMB)
Cynthia Khoo, graduate student, MD-PhD candidate (Pharmacology)
Jiangying Liu, PhD, Postdoctoral Researcher
Scott Soleimanpour, MD, Postdoctoral Researcher, Endocrinology
Fellow
Ada Po Man Suen, PhD, Postdoctoral Researcher
You Wang, Postdoctoral Researcher
Daniella Babu, Postdoctoral Researcher
Hong Yan, PhD, Visiting Scientist
Alana Ferrari, Undergraduate
last updated 8/2008
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