Premature Aging, Vascular Disease and Endothelial Mechanotransduction

过早衰老、血管疾病和内皮机械传导

• 批准号: 7910947
• 负责人: William James Adams
• 金额: $ 4.12万
• 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: 2010-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910947
• 关键词: Adult; Affect; Aging; Alopecia; Appearance; Arteries; Atherosclerosis; Biomechanics; Blood Vessels; Cell model; Critical Pathways; Defect; Development; Disease; Endothelial Cells; Endothelium; Ensure; Event; Familial Hypercholesterolemia; Fibroblasts; Functional disorder; Genetic Programming; Harvest; Heart; Human; Impairment; Investigation; Laboratories; Light; Modeling; Molecular; Mutation; Myocardial Infarction; Osteoporosis; Pathogenesis; Patients; Phenotype; Premature aging syndrome; Progeria; Research; Resistance; Risk; Risk Factors; Signal Pathway; Skin Wrinkling; Stimulus; Stroke; Syndrome; Testing; Trees; Vascular Diseases; Vascular Endothelium; Werner Syndrome; Work; age related; apolipoprotein B-100; atherogenesis; atheroprotective; base; body system; early onset; fluid flow; induced pluripotent stem cell; insight; normal aging; premature atherosclerosis; public health relevance; response; shear stress

DESCRIPTION (provided by applicant): Premature aging syndromes are the result of several identified rare mutations leading to the dysfunction of multiple organ systems characterized by features of normal aging such as osteoporosis, alopecia and skin wrinkling. Patients with Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner's Syndrome (WS) for example, are affected by accelerated, premature atherosclerosis leading to heart attacks and strokes. Just as monogenic diseases such as familial hypercholesterolemia and familial defective apoB-100 have provided powerful molecular insights into the pathogenesis of atherosclerosis, premature aging syndromes may offer an opportunity to expose new critical pathways involved in atherogenesis. While several lines of investigation have begun to probe the vascular defects associated with these syndromes, the involvement of vascular endothelium in the pathogenesis of the vascular disease associated with HGPS and WS remains unexplored. Our laboratory and others have shown that endothelial dysfunction, which constitutes a multi- faceted impairment of the vital functions of the lining of the heart and blood vessels, is an early critical event in the development of vascular disease. We have shown that this dysfunction can be caused by the presence or absence of biomechanical stimuli. Biomechanical forces are important players in endothelial function, particularly in evoking atherosclerosis-resistant or atherosclerosis-susceptible phenotypes depending on the specific biomechanical stimulus. These distinct cellular phenotypes are the result genetic programs activated by specific mechanosensitive signaling pathways in response to atheroprotective or atheroprone shear stress present in the human arterial tree. Based on these observations, biomechanical forces can be considered "local risk factors" in atherogenesis. Here, it is my working hypothesis that the early appearance of atherosclerosis in premature aging syndromes is a consequence of dysfunctional endothelial cell responsiveness to atheroprotective shear stress. To test this hypothesis, in Specific Aim 1, we will first create induced pluripotent stem (iPS) cells from fibroblasts that have been harvested from normal, HGPS and WS human patients. In Specific Aim 2, we will differentiate these iPS cells into endothelium. We will rigorously characterize this endothelium both structurally and functionally to ensure it has a mature, arterial identity. Assured of this, in Specific Aim 3, we will subject the normal and premature aging model iPS cell-derived endothelium to shear stress waveforms present in the adult human vasculature and assess the resulting endothelial phenotype. This will indicate whether the premature aging model endothelium is predisposed atherosclerosis due to dysfunctional mechanotransduction. PUBLIC HEALTH RELEVANCE: We will study the mechanism responsible for the increased risk of vascular disease during aging. To approach this, we will work with cells modeling two premature aging diseases, namely Hutchinson- Gilford Progeria Syndrome and Werner's Syndrome and research their ability to respond to fluid flow as in human arteries. Studying the early onset of vascular disease in premature aging syndromes may shed light on the age-related causes of vascular diseases in general.

描述（由申请人提供）：早衰综合征是几种鉴定的罕见突变的结果，导致多器官系统功能障碍，其特征为正常衰老的特征，如骨质疏松症、脱发和皮肤老化。例如，患有Hutchinson-Gilford早衰综合征（HGPS）和Werner综合征（WS）的患者受到加速的过早动脉粥样硬化的影响，导致心脏病发作和中风。正如单基因疾病如家族性高胆固醇血症和家族性apoB-100缺陷为动脉粥样硬化的发病机制提供了强有力的分子见解一样，过早衰老综合征可能提供了一个机会，以揭示动脉粥样硬化形成中涉及的新的关键途径。虽然几条线的调查已经开始探索与这些综合征的血管缺陷，血管内皮细胞的参与与HGPS和WS相关的血管疾病的发病机制仍然是未知的。 我们的实验室和其他实验室已经表明，内皮功能障碍是血管疾病发展的早期关键事件，内皮功能障碍构成了心脏和血管内膜重要功能的多方面损害。我们已经证明，这种功能障碍可能是由生物力学刺激的存在或不存在引起的。生物力学力是内皮功能的重要参与者，特别是在唤起动脉粥样硬化抵抗或动脉粥样硬化易感的表型，这取决于特定的生物力学刺激。这些不同的细胞表型是响应于存在于人动脉树中的动脉粥样硬化保护或动脉粥样硬化酮剪切应力而由特定的机械敏感性信号传导途径激活的遗传程序的结果。基于这些观察结果，生物力学力可以被认为是动脉粥样硬化形成中的“局部风险因素”。在这里，我的工作假设是，过早衰老综合征中动脉粥样硬化的早期出现是内皮细胞对动脉粥样硬化保护剪切力的功能障碍的结果。 为了验证这一假设，在特定目标1中，我们将首先从正常、HGPS和WS人类患者中收获的成纤维细胞中创建诱导多能干（iPS）细胞。在具体目标2中，我们将这些iPS细胞分化为内皮细胞。我们将在结构和功能上严格表征这种内皮，以确保其具有成熟的动脉特性。为了确保这一点，在特定目标3中，我们将使正常和过早老化模型iPS细胞衍生的内皮经受成人血管系统中存在的剪切应力波形，并评估所得内皮表型。这将指示过早老化模型内皮是否由于功能失调的机械转导而易患动脉粥样硬化。 公共卫生相关性：我们将研究衰老过程中血管疾病风险增加的机制。为了解决这个问题，我们将与细胞建模两种过早衰老的疾病，即哈钦森-吉尔福德早衰综合征和沃纳综合征和研究他们的能力，以响应流体流动，在人类动脉。研究过早衰老综合征中血管疾病的早期发病可能会揭示血管疾病的年龄相关原因。