Over the past few years, we have constructed large combinatorial chemical libraries [2] (>100,000 diverse and discrete small molecules) and carried out high throughput phenotypic screens of these libraries to identify small molecules that can control stem cell fate in several systems (introduced in Section B) [3]. Here we propose to develop and implement a high throughput screen of 100,000 diverse and discrete compounds to identify small molecules that can selectively induce differentiation of human embryonic stem cells (hESCs) [NIH registry code: WA01] into cardiac muscle precursor cells (which can further differentiate into beating cardiomyocytes). We will further confirm and characterize their effects and activities via various in-depth cellular/biochemical assays, and carry out structure-activity-relationship (SAR) studies of the selected hit compounds to optimize their potency and specificity. Collectively, the studies described in this proposal will provide novel chemical tools for producing human cardiac muscle precursors from hESCs for various applications, as well as studying the signaling pathways controlling cardiac specification, and may ultimately facilitate development of small molecule therapeutics to treat cardiovascular diseases, and/or stimulate cardiac regeneration in vivo. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL084295-02
Application #
7337327
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2007-01-01
Project End
2008-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
2
Fiscal Year
2008
Total Cost
$331,625
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Xu, Yue; Shi, Yan; Ding, Sheng (2008) A chemical approach to stem-cell biology and regenerative medicine. Nature 453:338-44