Investigating the role of Hopx in cardiac progenitor proliferation

描述(由申请人提供)：该提案描述了一项为期五年的培训计划，旨在发展心血管生物学的研究生涯。这位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。这项拟议的研究将在乔纳森·A·爱泼斯坦医学博士的指导下进行，他是心脏开发领域的领导者，曾培训过许多年轻的研究人员。还成立了一个由有才华的医生和科学家组成的咨询委员会，提供职业发展和科学方面的指导。研究环境提供了广泛的资源、核心设施和智力专长。因此，这是一个理想的培训环境，以发展必要的技能，以过渡到一个独立的内科医生科学家。参加教学课程和专业发展研讨会将提高该计划的教育成功。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，因为它是从增生性生长过渡到肥厚性生长的窗口。最近的研究表明，这也是心脏损伤后可以再生心肌细胞的时间段。因此，深入了解这些进程可能会引起相当大的兴趣。Hopx是一种转录辅助因子，并且一组Hopx缺失的胚胎表现出妊娠晚期心肌细胞的增殖，这表明Hopx在调节胚胎心肌细胞的增殖中起着关键作用。然而，Hopx与之相互作用的蛋白质及其调控心肌细胞增殖的转录程序在很大程度上仍然是一个谜。候选人开发的新的遗传工具将促进这些过程的研究，该提议的目的是：1.检验Hopx是胚胎心肌细胞NuRD复合体的一个亚单位的假设。2.验证含有Hopx的复合体通过直接结合增殖相关基因的调控区来抑制胚胎心肌细胞增殖的假设。3.验证HDAC2和Hopx之间的相互作用在体内以组织特异性的方式具有功能后果，从而促进Hopx介导的肥大的假设。最近的研究还发现，在成人肠道和毛囊干细胞中有特异性的Hopx表达。因此，预计从 对这些特征良好的群体进行调查，再加上对胚胎心脏前体细胞的机制研究，将为申请者成功成为解剖成人心脏再生反应的独立科学家奠定坚实的平台。

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.