Molecular regulation of heart valve development and function.

心脏瓣膜发育和功能的分子调节。

• 批准号: 8388794
• 负责人: Joy Lincoln
• 金额: $ 24.36万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8388794
• 关键词: Molecular; regulation; heart; valve; development

DESCRIPTION (provided by applicant): Heart valve disease, including structural malformations, is the leading cause of mortality in adults. Despite the clinical relevance, the molecular mechanisms required for heart valve formation and function are not well defined. Normal mature heart valve leaflets and supporting structures are differentially composed of diversified extracellular matrix and cell lineages organized to facilitate normal valve function. In contrast, diseased or malfunctioning valves display drastic alterations in connective tissue distribution. We have shown that mature valve supporting structures express the bHLH transcription factor scleraxis and genes associated with tendon cell types. In contrast, valve leaflets express markers related to cartilaginous cell lineages. These specialized cell types are derived from a common population of undifferentiated precursor cells and we have reported that signaling pathways important for valve precursor cell differentiation in vitro are common with tendon and cartilage development. Using an avian in vitro system developed in our lab we have generated data to suggest that ERK1/2-Smad1/5/8 signaling, and activation of downstream scleraxis, are important for valve precursor cell determination and differentiation of a tendon-like lineage that forms valve supporting structures. However further work is required to define these regulatory hierarchies in the development and maintenance of diversified valve structures. Therefore, experiments in avian valve cells in vitro will be used to determine the consequences of altered ERK1/2 and scleraxis function on lineage differentiation in valve precursors and mature valve cells. In addition, generated mice with conditional loss of scleraxis function in vivo will determine the requirements of scleraxis for valve formation and function. The specific aims of the proposed project are to: 1. Determine if antagonistic ERK1/2 and Smad1/5/8 signaling regulates valve precursor cell fate to promote differentiation of tendon- or cartilage-like cell types. 2. Determine if scleraxis is necessary and sufficient to promote tendon-like cell differentiation in valve precursor cells and maintain extracellular matrix organization in mature valve structures. 3. Determine if scleraxis is required for tendon-like cell differentiation and formation of supporting valve structures in vivo. Testing this hypothesis will determine molecular mechanisms important for normal valve development and maintenance. In addition proposed studies will identify regulatory interactions that may underlie congenital valve disease and adult valve degeneration associated with alterations in connective tissue composition and distribution. PUBLIC HEALTH RELEVANCE. Heart valve defects occur in at least 5 million individuals in the United States and the incidence of valve disease is increasing with over 95,0000 surgical procedures to repair or replace malformed valves performed in the US in 2003. However current valve alternatives are limited and often temporary due to inappropriate replacements that fail to grow, remodel, repair or withstand life-long demands. Increased understanding of the processes required for valve development and maintenance has potential clinical significance in identifying genes associated with congenital heart disease and adult valve degeneration, as well as advancing current therapeutic applications.

描述（由申请人提供）：心脏瓣膜疾病，包括结构畸形，是成人死亡的主要原因。尽管具有临床意义，但心脏瓣膜形成和功能所需的分子机制尚未明确。正常成熟的心脏瓣膜小叶和支持结构由组织化以促进正常瓣膜功能的多样化细胞外基质和细胞谱系组成。相比之下，病变或功能失常的瓣膜显示结缔组织分布的急剧变化。我们已经证明，成熟的瓣膜支持结构表达bHLH转录因子scleraxis和与肌腱细胞类型相关的基因。相反，瓣膜小叶表达与软骨细胞谱系相关的标记物。这些特化的细胞类型来自未分化的前体细胞的共同群体，并且我们已经报道了对瓣膜前体细胞体外分化重要的信号传导途径与肌腱和软骨发育是共同的。使用我们实验室开发的禽类体外系统，我们已经产生的数据表明，ERK 1/2-Smad 1/5/8信号传导和下游巩膜轴的激活对于瓣膜前体细胞的确定和形成瓣膜支撑结构的肌腱样谱系的分化是重要的。然而，需要进一步的工作，以确定这些监管层次的发展和维护多样化的瓣膜结构。因此，将使用体外禽类瓣膜细胞实验来确定改变的ERK 1/2和硬化轴功能对瓣膜前体和成熟瓣膜细胞谱系分化的影响。此外，体内产生的有条件丧失巩膜轴功能的小鼠将决定巩膜轴对瓣膜形成和功能的要求。拟议项目的具体目标是：1.确定是否拮抗ERK 1/2和Smad 1/5/8信号调节瓣膜前体细胞的命运，以促进肌腱或软骨样细胞类型的分化。2.确定硬化是否是促进瓣膜前体细胞中肌腱样细胞分化和维持成熟瓣膜结构中细胞外基质组织的必要和充分条件。3.确定体内肌腱样细胞分化和支持瓣膜结构形成是否需要硬化。验证这一假设将确定正常瓣膜发育和维护的重要分子机制。此外，拟定的研究将确定可能导致先天性瓣膜疾病和成人瓣膜退行性变（与结缔组织组成和分布改变相关）的调节相互作用。公共卫生相关性。在美国至少有500万人发生心脏瓣膜缺陷，并且瓣膜疾病的发病率正在增加，2003年在美国进行了超过95，0000例外科手术以修复或置换畸形瓣膜。然而，目前的瓣膜替代品是有限的，并且通常是暂时的，这是由于不适当的更换无法生长、改造、维修或承受终身需求。增加对瓣膜发育和维护所需过程的理解，对于识别与先天性心脏病和成人瓣膜退行性变相关的基因以及推进当前的治疗应用具有潜在的临床意义。