Wnt/Beta-catenin and Tcf/Lef factor regulation of pluripotency

Wnt/β-连环蛋白和 Tcf/Lef 因子对多能性的调节

• 批准号: 8775490
• 负责人: Bradley J Merrill
• 金额: $ 32.03万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775490
• 关键词: Address; Adult; Affect; Automobile Driving; Back; Beryllium; Binding; Binding Sites; Cardiac; Cell Differentiation process; Cell Therapy; Cell model; Cells; Characteristics; Clustered Regularly Interspaced Short Palindromic Repeats; Commit; DNA Binding; Data; Defect; Development; Developmental Biology; Elements; Embryo; Embryonic Development; Enhancers; Epigenetic Process; Exhibits; Formaldehyde; Foundations; Gene Expression; Genes; Genome; Genomics; Goals; Health; In Vitro; Indium; Knowledge; Maintenance; Maps; Measures; Molecular Biology; Mus; Oncogenic; Outcome; Phase; Physiological; Process; Property; Proteins; Protocols documentation; Regenerative Medicine; Regulation; Regulatory Element; Research; Role; Safety; Signal Transduction; Site; Specific qualifier value; Staging; Stem cells; Testing; Therapeutic; Work; base; beta catenin; cell type; drug development; embryonic stem cell; extracellular; gastrulation; human disease; in vivo; insight; mutant; pluripotency; relating to nervous system; response; self-renewal; stem; stem cell biology; stem cell fate; transcription factor

DESCRIPTION (provided by applicant): Previous groundbreaking discoveries have made it possible to grow pluripotent embryonic stem (ES) cells in vitro and to reprogram adult cells back to a pluripotent state. These advances have opened new opportunities for regenerative medicine by providing the cellular starting point from which we can derive adult cell types with physiological properties to study and treat human disease. Attaining cell types suitable for direct therapeutic application or as cellular models of human disease for drug development both require a substantial level of similarly to the in vivo cellular counterpart. Most often, investigaors attempt to attain the best in vivo mimics by replicating key aspects of a cell's developmental progression through embryogenesis. Given the appreciation that epigenetic effects are cumulative and progressive through embryogenesis, a central hypothesis of this proposal is that the initial steps in lineage specification are critical, and epigenetic mistakes made during exit from pluripotency can have undesirable effects even after cells have reached the targeted differentiated state. To address this problem, we aim to elucidate the mechanisms that eliminate or "decommission" ES cell- specific gene regulatory elements (i.e. enhancers) from lineage specified cell types. We discovered that a sequence-specific DNA-binding transcription factor, Tcf7l1, binds specifically to enhancers in ES cells that are targeted for decommissioning. Given our previous findings that showed Tcf7l1 stimulated differentiation of ES cells, we propose testing the hypothesis that Tcf7l1 is necessary to decommission ES specific enhancers. The proposal will further determine how this effect of Tcf7l1 changes the responses of cells to extracellular signals, and measure how important it is for genuine lineage specification using established in vitro differentiation protocols. The immediate outcome of completing the proposed research will be a better understanding of how cells exit the pluripotent state, and a demonstration of how defects during early steps can diminish the efficiency of subsequent stages of differentiation. Finally, given the oncogenic potential of accessible ES- specific enhancers in adult cells, the importance of the proposed work for increasing the safety of cell-based therapies should be appreciated.

描述（由申请人提供）：以前的突破性发现使得体外培养多能性胚胎干细胞（ES）和重编程成体细胞回到多能状态成为可能。这些进步为再生医学开辟了新的机会，提供了细胞的起点，我们可以从中获得具有生理特性的成年细胞类型，以研究和治疗人类疾病。获得适合直接使用的细胞类型