The goal of this proposal for activating the independent phase (ROO) stays the same as that of the original proposal for the award, i.e., to generate a novel and Integrated view of the mechanisms of hematopoietic precursor self-renewal and differentiation using EML (erythroid, myeloid, and lymphocytic) multipotential cells as a model system. EML cells are ideal for studying the molecular control of early hematopoietic differentiation at a large scale. EML cells give rise to the self-renewing CD34+ precursor cells and partially differentiated non-renewing CD34- cells. Large quantities of EML cells can be grown and differentiated in vitro in the absence of an anatomical niche. Based on my K99 phase of study in differential gene expression, and of transcription factor binding using Chip-Sequencing, I hypothesize that there are key regulators in transcriptional regulatory networks determining the choice between EML cell self-renewal and differentiation, such as TCF7 and RUNX1. I have already constructed preliminary transcriptional regulatory circuits regulated by TCF7 and RUNXI. For my ROO phase of research, 1 plan to globally identify the key transcriptional regulators controlling EML cell self-renewal and differentiation by using gene expression and proteomic data to guide the transcriptional regulation work. The binding targets and transcription factors will be assembled into regulatory networks and I will identify target hubs and test for master regulators. Subsequently I will integrate our genomic, proteomics, phosphorylation data and literature into the transcription factor binding networks and further develop a global interaction network. Finally I will confirm key findings in human primary cells. The proposed project can lead to molecular and biochemical studies in my own lab for many years to come.

Public Health Relevance

These studies in EML cells will demonstrate fundamental properties of self-renewal and differentiation mechanisms available to stem cells which hold great promise in repairing or regenerating damaged tissues and organs. Molecular understanding gained through this study will hopefully improve Durability to direct hematopoietic stem cell (HSC) fate by, for example, replicating and differentiating HSCs in vitro. Therefore, this study is highly valuable for public health and therapeutic purposes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL093213-06
Application #
8511424
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mondoro, Traci
Project Start
2011-08-20
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2013
Total Cost
$225,289
Indirect Cost
$69,266
Name
University of Texas Health Science Center Houston
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225