Twist1 regulation of valve progenitors

描述(由申请人提供)：心脏瓣膜置换术是美国第二常见的心脏手术，而作为钙化指标的主动脉瓣硬化发生在25%的老年人身上。最近的发现已经确定了瓣膜发育和成人疾病中常见的分子相互作用。然而，瓣膜再生或修复的细胞基础尚未确定。初步研究表明，bHLH转录因子Twist1促进瓣膜祖细胞的增殖和迁移，同时抑制分化。在正常发育过程中，Twist1的表达在瓣膜重塑过程中下调，在正常成人瓣膜中检测不到Twist1的表达。然而，Twist1在病变的人类瓣膜中的表达增加，在细胞增殖和ECM紊乱的区域，支持Twist1在成人瓣膜发病和潜在修复中的作用。我们假设Twist1在胚胎发育和出生后瓣膜发病过程中促进瓣膜祖细胞的增殖并抑制分化，从而维持祖细胞的数量。建议的研究将剖析心脏瓣膜发育和疾病中瓣膜祖细胞生成和维持的细胞和分子机制。目的是1)确定Twist1同源和异源二聚体在瓣膜祖细胞的增殖、迁移和分化中是否具有不同的功能。2)确定Twist1的表达是否足以通过在胚胎瓣膜发育后期和成熟成熟瓣膜中诱导EMT和细胞增殖来产生瓣膜前体细胞。3)确定与Twist1诱导的人类瓣膜疾病相关的病理学，并确定Twist1的表达是否能阻止小鼠心脏瓣膜疾病的进展。这些研究的长期目标是定义心脏瓣膜细胞谱系发育中的关键调控途径，并识别潜在的再生机制，用于瓣膜疾病的治疗。 公共卫生相关性：心脏瓣膜畸形是最常见的出生缺陷类型之一，成人瓣膜疾病是美国发病率和死亡率的重要原因。我们的研究将检验转录因子Twist1在正常瓣膜发育中促进祖细胞形成和扩张的能力。我们还将确定Twist1是否在成人瓣膜疾病中发挥作用，在抑制病理性钙化的同时促进细胞增殖。

DESCRIPTION (provided by applicant): Heart valve replacement is the second most common cardiac surgery in the United States, and aortic valve sclerosis, an indicator of calcification, occurs in >25% of aged individuals. Recent findings have established common molecular interactions in valve development and adult disease. However, a cellular basis for valve regeneration or repair has not yet been identified. Preliminary studies demonstrate that the bHLH transcription factor Twist1 promotes proliferation and migration while inhibiting differentiation of valve progenitor cells. During normal development, Twist1 expression is downregulated during valve remodeling, and expression is undetectable in normal adult valves. However, Twist1 expression is increased in diseased human valves in regions with increased cell proliferation and ECM disorganization, supporting a role for Twist1 in adult valve pathogenesis and potentially repair. We hypothesize that Twist1 promotes valve progenitor cell proliferation and inhibits differentiation, thereby maintaining the progenitor population, during embryonic development and postnatal valve pathogenesis. The proposed studies will dissect the cellular and molecular mechanisms of valve progenitor generation and maintenance in heart valve development and disease. The aims are 1) Determine if Twist1 homo- and hetero-dimers have differential functions in valve progenitor cell proliferation, migration and differentiation. 2) Determine if Twist1 expression is sufficient to generate valve progenitors by inducing EMT and cell proliferation in late stages of embryonic valve development and in mature adult valves. 3) Define the pathology associated with Twist1 induction in human valve disease and determine if Twist1 expression prevents valve disease progression in mice. The long-term goals of these studies are the definition of critical regulatory pathways in heart valve cell lineage development and the identification of potential regenerative mechanisms with therapeutic applications in valve disease. PUBLIC HEALTH RELEVANCE: Heart valve malformations are among the most common types of birth defects and adult valve disease is a significant cause of morbidity and mortality in the United States. Our studies will examine the ability of the transcription factor Twist1 to promote the formation and expansion of progenitor cells in normal valve development. We also will determine if Twist1 functions in adult valve disease to promote cell proliferation while inhibiting pathological calcification.