Grants and Contracts Details
Description
Our long-term goal Is to understand the molecular mechanisms of gene regulation by the
transcription factors governing b-cell development and function, and the molecular basis of
diabetes-causing mutations found in them. We have chosen HNFla as a model system which has
been identified as a culprit gene product for MODY3.HNFla ISa master switch in b-cell
differentiation, growth and function, and its mutations accounts for the majority of MODYcases.
Numerous point mutations are found in HNFla and they could be instructive as to the mechanism
of transcription regulation and how the mutations disrupt the normal function at the molecular
level. As a gene-specific transcription factor, HNFla initiates transcription by specifically
recognizing the promoter region of target genes and mediating interactions with a host of
coregulators. However, detailed structural information on the assembly of higher-order
transcription complexes is not well known. Therefore, we propose to (1) solve the crystal structure
of HNFla in complex with its target DNAand DeaH, (2) solve the crystal structure of HNFla in
complex with its target DNAand p300, (3) identify additional b-cell specific transcriptional
coregulators for structural studies, and (4) examine the biological, biochemical and biophysical
effects of diabetes-causing mutations. These findings should aid overall understanding of
transcrIption control Involved In b-cell deveopment and function, and rational targeting of HNFla
in order to modulate Its activities for promoting maturation, prolonging survival and boosting
Insulin secretion, and to reverse the adverse effects by the mutations, thus potential treatment for
diabetes.
General Audience Summaryl
People with either a low level of fully-developed or defective mature b-cells would need b-cell
replacement or b-cell function boost to maintain glucose homeostasis. There is a network of
transcription factors controlling proper development and normal function of b-cells through their
ability to turn on or off specific genes during the critical times. When these transcription factors
are defective, Improper development and function of b-cell occur as in the case of genetic
mutations In HNFla which cause a inherited dominant form of diabetes known as MODY.
Therefore, a better understanding of islet factors that control development could provide new and
better ways to promote maturation, prolong survival and boost Insulin secretion in improperlydeveloped,
transplanted and/or engineered islet cells. We have been studying (thanks to the
JDRFI postdoc fellowship) how HNFla functions and how diabetes mutations disrupt Its functions
at the molecular level using a method called x-ray crystallography. This technique allows us to
visualize the action of this master switch in three dimensions at high resolution. Since HNFla
interacts with DNAand a host of proteins to form a transcription initiation complex and carries out
its functions, we propose to determine some of the structures of these higher-order complexes.
These structures should enhance our understanding of transcription control involved in b-cell
deveopment and function, and rational drug targeting of HNFla in order to modulate its activities
for enhancement of b-ce" growth and preservation of b-cell function, and to reverse the adverse
effects by the mutations, thus potential treatment for diabetes.
Status | Finished |
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Effective start/end date | 9/1/04 → 8/31/05 |
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