PROGERIN ENDOTHELIAL DYSFUNCTION AND VASCULAR DISEASE

早老素内皮功能障碍和血管疾病

• 批准号: 8514460
• 负责人: MICHAEL A GIMBRONE
• 金额: $ 29.98万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514460
• 关键词: Affect; Age; Aging; Aging-Related Process; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Arterial Fatty Streak; Arteries; Atherosclerosis; Birth; Blood Vessels; Cardiovascular Diseases; Cell physiology; Cells; Child; Chronic; Complex; Country; Defect; Development; Diagnosis; Disease; Documentation; Endothelial Cells; Event; Functional disorder; Future; Gene Expression; Gene Mutation; General Population; Genes; Genetic; Goals; Heart; Heart Diseases; Human; Hyperlipidemia; Impairment; In Vitro; Individual; Interleukin-1; Investigation; Laboratories; Lamin Type A; Lead; Link; Maintenance; Medial; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Mus; Mutation; Myocardial Infarction; Natural History; Nature; Nuclear Lamina; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Play; Point Mutation; Premature aging syndrome; Progeria; Proteins; Public Health; Research; Role; Signal Pathway; Signal Transduction Pathway; Smooth Muscle Myocytes; Stroke; Syndrome; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Translating; United States; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vascular remodeling; Viral; Work; autocrine; base; body system; defined contribution; design; genome-wide; human disease; in vitro Model; in vivo; in vivo Model; innovation; insight; mouse model; mutant; novel; novel therapeutics; overexpression; paracrine; premature; prevent; programs; public health relevance; research study; response

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.

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）的单基因形式的研究可以极大地帮助阐明其发病机制。最近对哈钦森-吉尔福德早衰综合症（HGPS）遗传基础的发现提供了这样的机会。 HGPS 是一种早衰症，受影响的儿童出生时外表正常，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 最突出和最致命的特征是过早和加速动脉粥样硬化，导致心脏病和中风。 HGPS 是由 LMNA 基因中的单点突变引起的，该突变导致称为 Progerin 的核纤层蛋白 A 蛋白突变形式的积累。该项目的中心假设是早老素在血管内皮中的积累会导致慢性内皮功能障碍，从而导致 HGPS 患者以及正常衰老个体中记录的血管病变的发生。在第一个具体目标中，我们将剖析表达早衰蛋白的培养 EC 中激活的导致慢性内皮功能障碍的分子途径。在第二个具体目标中，我们将阐明内皮源性早衰素刺激介质（例如白介素-1）对血管平滑肌细胞产生的旁分泌作用。在第三个具体目标中，我们将在新型转基因小鼠模型中研究早衰素体内内皮特异性表达的病理生理学后果。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，并可能为内皮功能障碍发挥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：多种人类疾病与衰老有关；其中包括动脉粥样硬化及其后果、心脏病和中风。特定基因发生基因突变的儿童会出现一种称为早衰症的早衰综合症。他们会形成动脉粥样硬化斑块，并且容易患心脏病和中风。我们建议了解这种突变如何引发早衰症儿童发生心血管疾病。这些涉及与血管疾病发展相关的特定基因的研究结果有望指明治疗早衰症儿童的新方法，并可能带来诊断、预防和治疗普通人群心脏病的创新策略。