Cell fate is determined by sets of genes that are expressed in a programmed manner during development and cellular differentiation. Often, in diseases as diverse as diabetes and cancer, malfunctioning transcriptional regulators produce aberrant patterns of gene expression that are at the heart of the ailment. How regulatory proteins find their binding sites and regulate their targeted genes remains a central question in the field. ? ? We combine chemical and biological approaches to study otherwise intractable features of transcriptional regulators. We utilize sequence-specific DNA binding compounds (polyamides) to target specific DNA sequences, and they can be readily modified to bear a rich array of functional modules. In the proposed work, we will elucidate the basis of cooperative DNA binding by Extradenticle and Ultrabithorax, two highly conserved developmental regulators. We will apply that understanding to develop precisely tailored synthetic regulators that target genes cooperatively with cell-type specific transcription factors. Finally, we will test the ability of our artificial transcription factors to regulate genes in cells and in living organisms. ? ? The ultimate goal of our work is to generate small molecules that can regulate the expression of targeted genes in a desired manner. As designer transcription factors, these molecules will have tremendous value in dissecting transcriptional networks that govern cell fate and disease. They also have potential as therapeutic agents for a variety of diseases that are caused by aberrant transcriptional regulation. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM069420-01A1
Application #
7030370
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Tompkins, Laurie
Project Start
2006-01-01
Project End
2010-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
1
Fiscal Year
2006
Total Cost
$252,561
Indirect Cost
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Ozers, Mary S; Warren, Christopher L; Ansari, Aseem Z (2009) Determining DNA sequence specificity of natural and artificial transcription factors by cognate site identifier analysis. Methods Mol Biol 544:637-53

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