MECHANISTIC BASIS FOR REGIONAL PREDISPOSITION FOR ANEURYSM

动脉瘤是血管中的局灶性扩张，估计占工业化国家所有死亡的1-2%。 国家没有有效的药物治疗来防止破裂，唯一的治疗选择是 预防性手术修复对动脉瘤高风险单基因疾病的研究已经确定， 发病机制中的关键成分，包括调节发育和稳态的信号通路 以及调节细胞外基质组装和功能的蛋白质。在两 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拉克萨1B型 （ARCL 1B），血管紧张素II（AngII）受体I（AT 1 R）信号通路的过度激活已被证实。 被认为是动脉瘤的常见下游驱动因素。LDS是由突变引起的， 完全消除转化生长因子-β（TGF-β）信号传导; ARCL 1B是由纯合的 细胞外基质蛋白fibulin-4（EFEMP 2/FBLN 4）中的功能突变。尽管这些条件是 由于普遍表达的基因突变，疾病主要发生在主动脉根部， LDS和ARCL 1B中更远端的升主动脉。没有分子解释存在这个区域 易感性对使某些区域易受或保护的过程的分子理解 动脉瘤可能会导致专门针对这些机制脆弱性的治疗方法的发展。 我们的前期工作表明，第二心野（SHF）源性平滑肌的胚胎学起源可能与其细胞的发育有关。 细胞，主要存在于主动脉根部，和心脏神经嵴（CNC）衍生的平滑肌细胞， 主要存在于升主动脉，定义了这些细胞对血管内皮细胞的影响的内在脆弱性。 导致LDS的突变使用LDS和ARCL 1B的小鼠模型，我们将测试中心假设，即局部 扩张的风险是由关键的基因与谱系的相互作用驱动的，这种相互作用扰乱了在健康情况下 个体，在生理上抑制平滑肌细胞中的AT 1 R信号传导。我们将结合使用 新的体内方法以及表观遗传和转录分析，以实现以下目的。在Aim中 1，我们将询问部分TGF-β信号丢失的时间是否以及如何影响动脉瘤 AT 1 R信号传导的发展和敏化。在目标2中，我们将研究致病作用， LDS小鼠模型中谱系特异性AT 1 R信号增强的机制。在目标3中，我们将使用 ARCL 1B小鼠模型，以检查平滑肌细胞的胚胎学起源是否以及如何改变 与fibulin-4缺陷相关的信号传导和转录结果。了解 使某些动脉区域易患疾病的机制有可能揭示基本的 血管生物学的各个方面，并为新疗法的开发提供信息。我们在分析 LDS小鼠模型中的谱系特异性事件，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.