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（如心肌梗死和中风），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，对某些类型血管疾病（如家族性高脂血症和动脉粥样硬化）的单基因形式的研究可以极大地帮助阐明其发病机制。最近发现的哈钦森-吉尔福德早衰综合征（HGPS）的遗传基础提供了这样一个机会。HGPS是一种早衰疾病，患儿出生时外观正常，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最显著和最致命的特征是过早和加速动脉粥样硬化，导致心脏病发作和中风。HGPS是由LMNA基因的单点突变引起的，这种突变会导致一种叫做Progerin的纤层蛋白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Progerin的积累导致慢性内皮功能障碍，导致HGPS患者的血管病变，也可能导致正常衰老个体的血管病变。在第一个具体目标中，我们将剖析在表达progerin的培养EC中激活的导致慢性内皮功能障碍的分子途径。在第二个特定目标中，我们将阐明内皮来源的、受早衰素刺激的介质（如白细胞介素-1）对血管平滑肌细胞的旁分泌作用。在第三个特定目的中，我们将在一种新的转基因小鼠模型中研究体内内皮特异性表达Progerin的病理生理后果。这些研究应该为HGPS患者血管疾病的细胞和分子原因提供重要的机制见解，并可能为其他内皮功能障碍起致病作用的血管疾病提供新的治疗策略。

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.