PROGERIN ENDOTHELIAL DYSFUNCTION AND VASCULAR DISEASE

描述（由申请人提供）：血管疾病，特别是动脉粥样硬化及其并发症（例如，心肌梗塞和中风）仍然是困扰美国和其他国家数百万人的主要公共卫生问题。鉴于其固有的复杂性和可变性，对某些类型的血管疾病（例如，家族性高脂血症和动脉粥样硬化）可以极大地帮助阐明它们的发病机制。最近发现的遗传基础的哈钦森-吉尔福德早衰症（HGPS）提供了这样一个机会。HGPS是一种过早衰老的疾病，其中受影响的儿童在出生时具有正常的外观，但在1-2年内开始迅速衰老。这种疾病影响多个器官系统，包括心脏和血管。事实上，HGPS最突出和致命的特征是过早和加速的动脉粥样硬化，导致心脏病发作和中风。HGPS是由LMNA基因中的单点突变引起的，其导致称为早老蛋白的核纤层蛋白A蛋白的突变形式的积累。该项目的中心假设是，血管内皮中的早老蛋白积累导致慢性内皮功能障碍，导致HGPS患者中记录的血管病理学的发作，并且可能也在正常个体中伴随衰老。在第一个具体的目标，我们将剖析分子通路激活的早老蛋白表达培养EC，导致慢性内皮功能障碍。在第二个具体的目标，我们将阐明旁分泌的影响，内皮源性，早老素刺激介质（如白细胞介素-1）对血管平滑肌细胞。在第三个具体的目标，我们将研究的病理生理后果的内皮特异性表达的早老蛋白在体内的一种新的转基因小鼠模型。这些研究将为HGPS患者血管疾病的细胞和分子原因提供重要的机制见解，并可能为内皮功能障碍起致病作用的其他血管疾病提出新的治疗策略。 公共卫生相关性：几种人类疾病与衰老有关;其中包括动脉粥样硬化及其后果、心脏病发作和中风。在特定基因中发生基因突变的儿童会患上一种名为早衰症的早衰综合症。他们发展动脉粥样硬化斑块，并容易发生心脏病发作和中风。我们建议了解这种突变如何触发早衰症儿童心血管疾病的发展。这些研究的结果涉及与血管疾病发展相关的特定基因，有望为治疗早衰症儿童提供新的方法，也可能导致诊断，预防和治疗普通人群心脏病的创新策略。

DESCRIPTION (provided by applicant): Vascular diseases, in particular atherosclerosis and its complications (e.g., myocardial infarction and stroke), continue to be a major public health problem that afflicts millions of people in the United States and other countries. Given their inherently complex and variable nature, the study of monogenic forms of some types of vascular disease (e.g., familial hyperlipidemias and atherosclerosis) can greatly assist in elucidating their pathogenesis. The recent discovery of the genetic basis of Hutchinson-Gilford Progeria Syndrome (HGPS) provides such an opportunity. HGPS is a premature aging disorder in which affected children have normal appearance at birth, but begin to age rapidly within 1-2 years. This disease affects multiple organ systems, including the heart and blood vessels. Indeed, the most prominent and fatal feature of HGPS is premature and accelerated atherosclerosis resulting in heart attacks and strokes. HGPS is caused by a single point mutation in the LMNA gene, which results in accumulation of a mutant form of the lamin A protein called Progerin. The central hypothesis of this project is that Progerin accumulation in vascular endothelium results in chronic endothelial dysfunction, contributing to the onset of vascular pathologies documented in patients with HGPS, and potentially also in normal individuals with aging. In the first specific aim, we will dissect the molecular pathways activated in Progerin-expressing cultured EC that lead to chronic endothelial dysfunction. In the second specific aim, we will elucidate the paracrine effects that endothelial-derived, Progerin- stimulated mediators (such as interleukin-1) exert on vascular smooth muscle cells. In the third specific aim, we will investigate the pathophysiological consequences of endothelial-specific expression of Progerin in vivo in a novel transgenic murine model. These studies should provide important mechanistic insights into the cellular and molecular causes of vascular disease in HGPS patients, and may suggest new therapeutic strategies for other vascular diseases in which endothelial dysfunction plays a pathogenic role. PUBLIC HEALTH RELEVANCE: Several human diseases are associated with aging; among these are atherosclerosis and its consequences, heart attacks and strokes. Children with a genetic mutation in a specific gene develop a syndrome of premature aging called Progeria. They develop atherosclerotic plaques, and are prone to heart attacks and strokes. We propose to understand how this mutation triggers the development of cardiovascular disease in children with Progeria. Results from these studies, involving a specific gene linked to the development of vascular disease, will hopefully indicate new ways to treat children with Progeria and may also lead to innovative strategies to diagnose, prevent, and treat heart disease in the general population.