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大最常见的心脏手术，主动脉瓣硬化是钙化的一个指标，在25%的老年人中发生。最近的研究发现在瓣膜发育和成人疾病中建立了共同的分子相互作用。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，同时抑制瓣膜祖细胞的分化。在正常发育过程中，Twist1的表达在瓣膜重塑过程中下调，在正常成人瓣膜中无法检测到其表达。然而，Twist1在患病人类瓣膜中细胞增殖和ECM破坏增加的区域表达增加，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增殖并抑制分化，从而维持祖细胞群。提出的研究将剖析瓣膜祖细胞的产生和维持在心脏瓣膜发育和疾病中的细胞和分子机制。目的是：1)确定Twist1同源二聚体和异二聚体在瓣膜祖细胞增殖、迁移和分化中是否具有不同的功能。2)在胚胎瓣膜发育晚期和成熟成人瓣膜中，通过诱导EMT和细胞增殖，确定Twist1的表达是否足以产生瓣膜祖细胞。3)明确人类瓣膜疾病中Twist1诱导的相关病理，并确定Twist1表达是否能阻止小鼠瓣膜疾病的进展。这些研究的长期目标是确定心脏瓣膜细胞谱系发育的关键调控途径，并确定瓣膜疾病治疗应用的潜在再生机制。

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.