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，主动脉瓣硬化（钙化的指标）发生在>25%的老年人中。最近的研究结果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，尚未确定瓣膜再生或修复的细胞基础。初步研究表明，bHLH转录因子Twist 1促进增殖和迁移，同时抑制瓣膜祖细胞的分化。在正常发育过程中，Twist 1表达在瓣膜重塑过程中下调，并且在正常成人瓣膜中检测不到表达。然而，Twist 1的表达增加，在患病的人瓣膜中的区域与增加的细胞增殖和ECM解体，支持Twist 1在成人瓣膜发病机制和潜在的修复中的作用。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增殖并抑制分化，从而维持祖细胞群。拟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Twist 1同源和异源二聚体在瓣膜祖细胞增殖、迁移和分化中是否具有差异功能。2)确定Twist1表达是否足以通过诱导胚胎瓣膜发育晚期和成熟成人瓣膜中的EMT和细胞增殖产生瓣膜祖细胞。3)定义与人类瓣膜疾病中Twist 1诱导相关的病理学，并确定Twist 1表达是否可预防小鼠瓣膜疾病进展。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，并确定潜在的再生机制与瓣膜疾病的治疗应用。

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.