MECHANISTIC BASIS FOR REGIONAL PREDISPOSITION FOR ANEURYSM

动脉瘤是血管中的局限性扩张，估计占工业化国家所有死亡人数的1-2%。 国家。目前还没有有效的药物疗法来预防破裂，唯一的治疗选择是 预防性手术修复。对具有高动脉瘤风险的单基因疾病的研究发现 发病机制中的关键组成部分，包括调节发育和动态平衡的信号通路 以及调节细胞外基质的组装和功能的蛋白质。分成两份 遗传性动脉瘤疾病、Loeys-Dietz综合征(LDS)和常染色体隐性遗传性皮肤松弛1B型 (ARCL1B)，血管紧张素II(AngII)受体I(AT1R)信号通路被过度激活。 被确认为动脉瘤的常见下游驱动因素。LDS是由损害但不会 完全取消转化生长因子-β(转化生长因子-β)信号转导；ARCL1B是由纯合子缺失引起的 细胞外基质蛋白-4(EFEMP2/FBLN4)的功能突变。尽管这些条件是 由无处不在的表达基因突变引起的疾病主要发生在 LDS和ARCL1B升主动脉更远端。对于这个区域，没有分子的解释 性情。对预置或保护某些区域的过程的分子理解 动脉瘤可能导致专门针对这些机械脆弱性的治疗方法的开发。 我们以前的工作表明，第二心区(SHF)来源的平滑肌的胚胎起源 细胞，主要发现于主动脉根部，以及心脏神经脊(Cnc)来源的平滑肌细胞， 主要发现于升主动脉，决定了这些细胞对血管内皮细胞的内在脆弱性。 导致腰椎间盘突出症的突变。使用LDS和ARCL1B的小鼠模型，我们将检验局部 扩张症的风险是由关键的基因-谱系相互作用驱动的，这些相互作用扰乱了健康人 生理上抑制血管平滑肌细胞中的AT1R信号。我们将结合使用 新的体内方法和表观遗传学和转录分析，以实现以下目标。在AIM 1，我们将询问部分转化生长因子-β信号丢失的时机是否以及如何影响动脉瘤 AT1R信号的发展和敏化。在目标2中，我们将研究致病作用和 LDS小鼠模型中谱系特异性AT1R信号增强的机制。在目标3中，我们将使用 一种ARCL1B的小鼠模型，以研究血管平滑肌细胞的胚胎起源是否以及如何改变 与纤蛋白-4缺乏相关的信号和转录后果。了解 使某些动脉区域易患疾病的机制有可能揭示根本 血管生物学方面的知识，并为新疗法的发展提供信息。我们在分析的经验 LDS小鼠模型中的特定血统事件，我们的初步数据，以及与 必要的计算技能使我们处于进行这些研究的独特地位。

Aneurysms are focal dilatations in blood vessels estimated to account for 1-2% of all deaths in industrialized countries. No effective pharmacological therapies exist to prevent rupture, and the only treatment option is prophylactic surgical repair. The study of monogenic diseases that carry a high risk for aneurysm has identified critical components in pathogenesis, including signaling pathways that regulate development and homeostasis of vascular cells, and proteins that regulate the assembly and function of the extracellular matrix. In two hereditary aneurysm disorders, Loeys-Dietz Syndrome (LDS) and autosomal recessive cutis laxa type 1B (ARCL1B), excessive activation of the angiotensin II (AngII) receptor I (AT1R) signaling pathway has been identified as the common downstream driver of aneurysm. LDS is caused by mutations that impair but don't completely abolish transforming growth factor-β (TGF-β) signaling; ARCL1B is caused by homozygous loss-of- function mutations in the extracellular matrix protein fibulin-4 (EFEMP2/FBLN4). Although these conditions are caused by mutations in ubiquitously expressed genes, disease predominantly develops in the aortic root in LDS and in the more distal ascending aorta in ARCL1B. No molecular explanation exists for this regional predisposition. A molecular understanding of the processes that predispose or protect certain regions from aneurysm may lead to the development of therapies that specifically target these mechanistic vulnerabilities. Our previous work indicates that the embryological origin of second heart field (SHF)-derived smooth muscle cells, found predominantly in the aortic root, and cardiac neural crest (CNC)-derived smooth muscle cells, found predominantly in the ascending aorta, defines the intrinsic vulnerability of these cells to the effects of an LDS-causing mutation. Using mouse models of LDS and ARCL1B, we will test the central hypothesis that local risk of dilation is driven by critical gene-by-lineage interactions that perturb processes that, in healthy individuals, physiologically suppress AT1R signaling in smooth muscle cells. We will use a combination of novel in vivo approaches and epigenetic and transcriptional analyses to accomplish the following aims. In Aim 1, we will interrogate whether and how the timing of partial TGF-β signaling loss affects aneurysm development and sensitization to AT1R signaling. In Aim 2, we will examine the pathogenic role and mechanisms of lineage-specific AT1R signaling enhancement in a mouse model of LDS. In Aim 3, we will use a mouse model of ARCL1B to examine if and how the embryological origin of smooth muscle cells modifies the signaling and transcriptional consequences associated with fibulin-4 deficiency. Understanding the mechanisms that predispose certain arterial regions to disease has the potential to uncover fundamental aspects of vascular biology, and inform the development of new therapies. Our experience in the analysis of lineage-specific events in a mouse model of LDS, our preliminary data, and strong collaborative team with the necessary computational skills make us uniquely positioned to conduct these studies.