Investigating the role of Hopx in cardiac progenitor proliferation

研究 Hopx 在心脏祖细胞增殖中的作用

• 批准号: 8566353
• 负责人: Rajan Jain
• 金额: $ 13.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566353
• 关键词: Adult; Advisory Committees; Alleles; Amino Acids; Basic Science; Binding; Binding Sites; Biochemistry; Biology; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiology; Cardiovascular system; Cell Differentiation process; Cell Proliferation; Cells; ChIP-seq; Complement; Complex; Core Facility; Coupled; DNA Binding; Data; Data Set; Development; Doctor of Medicine; Embryo; Embryonic Development; Environment; Epidemic; Epitopes; Equilibrium; Event; Exhibits; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Glean; Growth; Hair follicle structure; Healed; Heart; Heart Diseases; Heart Hypertrophy; Histone Deacetylase; Homeobox; Homeodomain Proteins; Hyperplasia; Hypertrophy; In Vitro; Injury; Intestines; Investigation; Knockout Mice; Light; Maps; Mediating; Mentorship; Molecular Biology; Morphogenesis; Mus; Muscle; Muscle Cells; Myocardial Infarction; Natural regeneration; NuRD complex; Nucleic Acid Regulatory Sequences; Organ; Organogenesis; Pathologic; Pennsylvania; Perinatal; Physicians; Physiological; Population; Pregnancy; Process; Program Development; Proteins; Regulation; Research; Research Personnel; Resources; Role; Science; Scientist; Serum Response Factor; Skin; Stem cells; Stress; Testing; Time; Tissues; Training; Training Programs; Transgenic Mice; United States; Universities; adult stem cell; base; career; career development; chromatin immunoprecipitation; clinically relevant; cofactor; cohort; healing; heart cell; heart function; homeodomain; in vivo; interest; novel; progenitor; programs; protein complex; public health relevance; regenerative; repaired; research study; response; skills; stem cell population; success; tool; transcription factor

DESCRIPTION (provided by applicant): The proposal describes a five-year training program for development of a research career in cardiovascular biology. The candidate is a cardiology fellow at the University of Pennsylvania, and is currently engaged in intensive basic science research. The proposed research will be carried out under the mentorship of Jonathan A. Epstein, M.D., a leader in the field of cardiac development who has trained numerous young investigators. An advisory committee of talented physician-scientists has also been assembled to offer guidance in career development and science. The research environment offers extensive resources, core facilities, and intellectual expertise. Therefore, it is an ideal trainin setting to develop the requisite skills in order to transition to an independent physician scientis. Participation in didactic courses and professional development seminars will enhance the educational success of the program. Organogenesis requires a fine balance between cell proliferation and differentiation. The perinatal heart is especially sensitive to this balance as tis is the window in which it transitions from proliferative to hypertrophic growth. Recent studies demonstrate that this is also the time period in which hearts can regenerate myocytes after injury. Therefore, an in-depth understanding of these processes is likely to be of considerable interest. Hopx is a transcription co-factor, and a cohort of Hopx-null embryos display late gestation cardiac myocyte hyperplasia, suggesting a critical role for Hopx in regulating embryonic myocyte proliferation. However, the proteins that Hopx interacts with and the transcriptional programs it regulates in modulating cardiac myocyte proliferation remain largely a mystery. Novel genetic tools developed by the candidate will facilitate investigation of these processes, and the aims of the proposal are: 1. Test the hypothesis that Hopx is a subunit of the NuRD complex in embryonic myocytes. 2. Test the hypothesis that Hopx-containing complexes function to inhibit embryonic myocyte proliferation by directly binding the regulatory regions of proliferation- related genes. 3. Test the hypothesis that the interaction between Hdac2 and Hopx is of functional consequence in vivo in a tissue specific manner and hence facilitates Hopx-mediated hypertrophy. Recent studies have also identified specific Hopx expression in adult intestine and hair follicle stem cells. Therefore, it is anticipated that concepts gleaned from the investigation of those well-characterized populations, coupled with mechanistic studies in embryonic cardiac progenitor cells will build a strong platform for the applicant to succeed as an independent scientist dissecting adult cardiac regenerative responses.

描述（由申请人提供）：该提案描述了一项为期五年的心血管生物学研究职业的培训计划。该候选人是宾夕法尼亚大学的心脏病学研究员，目前从事密集的基础科学研究。拟议的研究将在心脏发展领域的领导者乔纳森·阿普斯坦（Jonathan A. Epstein）的指导下进行，他培训了许多年轻的研究人员。才华横溢的医师科学家咨询委员会也已经组装，以在职业发展和科学方面提供指导。研究环境提供了广泛的资源，核心设施和智力专业知识。因此，这是发展必要技能以过渡到独立医师科学家的理想火车环境。参加教学课程和专业发展研讨会将增强该计划的教育成功。器官发生需要细胞增殖和分化之间的良好平衡。围产期心脏对这种平衡特别敏感，因为tis是它从增殖到肥厚的生长的窗口。最近的研究表明，这也是心脏在受伤后可以再生肌细胞的时期。因此，对这些过程的深入理解可能会引起极大的兴趣。霍普克斯是转录的共同因素，一组霍普克斯无效的胚胎显示出晚期妊娠心肌细胞增生，这表明HOPX在调节胚胎肌细胞增殖方面起着至关重要的作用。但是，HOPX与之相互作用的蛋白质以及它在调节心肌细胞增殖时所调节的转录程序仍然很大程度上仍然是一个谜。候选人开发的新遗传工具将促进对这些过程的研究，该提案的目的是：1。检验假设Hopx是胚胎肌细胞中NURD复合物的亚基。 2。检验以下假设：含Hopx的复合物功能通过直接结合增殖相关基因的调节区域来抑制胚胎肌细胞增殖。 3。检验以下假设：HDAC2与HOPX之间的相互作用在组织特定方式中是体内功能性后果，因此促进了Hopx介导的肥大。最近的研究还确定了成年肠和毛囊干细胞中的特定HOPX表达。因此，可以预见的是，概念从 对那些特征良好的人群的研究，再加上胚胎心脏祖细胞中的机械研究，将为申请人建立一个强大的平台，使申请人成为成功的独立科学家，解剖成人心脏再生反应。