A proteomic approach for understanding plaque rupture

描述(由申请人提供)：动脉粥样硬化是一种血管壁疾病，可导致心脏病发作、中风和肢体丧失。尽管在内科和外科治疗方面取得了重大进展，但动脉粥样硬化仍会导致显著的发病率和死亡率。由于人口老龄化和当前年轻人肥胖/糖尿病流行的后果(糖尿病是动脉粥样硬化的主要危险因素)，预计未来几十年，动脉粥样硬化对美国人民健康的影响将增加。该项目的长期目标是通过进一步阐明动脉粥样硬化的分子和细胞发病机制以及阐明抗动脉粥样硬化治疗的新靶点来降低动脉粥样硬化的发病率和死亡率。动脉粥样硬化会导致血管变窄，从而限制血液流动，引发胸腿痛，并限制体力活动。然而，与动脉粥样硬化相关的主要临床事件--心脏病发作和中风--主要是由于动脉粥样硬化斑块的物理破坏或“破裂”，从而形成血栓，这些血栓要么完全阻塞血管，要么破裂并阻塞斑块破裂部位下游的血管。斑块破裂被认为是由被称为蛋白酶的酶消化斑块蛋白造成的，这种酶削弱了斑块结构的完整性，导致斑块破裂。然而，人们对这一过程知之甚少，而且还不是任何特定药物治疗的目标。该项目旨在揭示蛋白水解酶导致斑块破裂的分子机制。有两个特定的目标：Aim 1使用我们实验室培育的转基因小鼠的血管作为斑块破裂的动物模型，Aim 2使用人类斑块组织。这两个目标都使用强大的新技术来测量蛋白质，检测蛋白质的消化，并澄清蛋白质之间具有生理意义的关系。我们将使用这些新技术在动物模型和人类斑块组织中研究斑块破裂的发病机制。我们希望为预防斑块破裂的治疗找到新的分子靶点。此外，在这两个目标中产生的数据将允许客观地评估小鼠模型与人类斑块破裂的相关性。因此，这些研究可能会验证一种常见的、临床上重要的、但知之甚少的人类疾病的有用动物模型。我们目标的实现将有助于阐明动脉粥样硬化斑块破裂的机制。我们从实验中获得的见解可能有助于开发预防心脏病发作和中风的新疗法。 公共卫生相关性：人类动脉中动脉粥样硬化斑块的破裂是心脏病发作和中风的最常见原因。导致动脉粥样硬化斑块破裂的生物学机制尚不清楚，这种认识的缺乏阻碍了可以预防斑块破裂、心脏病发作和中风的治疗方法的开发。该项目旨在确定动脉粥样硬化斑块破裂的途径，期望这一新知识将导致预防心脏病发作和中风的新疗法。

DESCRIPTION (provided by applicant): Atherosclerosis is a disease of the blood vessel wall that causes heart attacks, strokes, and loss of limbs. Despite major advances in medical and surgical management, atherosclerosis still causes significant morbidity and mortality. The impact of atherosclerosis on the health of the American people is expected to increase in the coming decades due to aging of the population and the consequences of the current obesity/diabetes epidemic among the young (diabetes is a major risk factor for atherosclerosis). The broad, long-term objective of this project is to decrease the morbidity and mortality of atherosclerosis by further clarifying its molecular and cellular pathogenesis, and by illuminating new targets for anti-atherosclerosis therapies. Atherosclerosis causes narrowing of blood vessels that restricts blood flow, precipitates chest and leg pains, and limits physical activity. However the major clinical events associated with atherosclerosis-heart attacks and strokes-are caused primarily by physical disruption or "rupture" of atherosclerotic plaques with consequent formation of blood clots that either completely block blood vessels or break free and block vessels downstream of the site of plaque rupture. Plaque rupture is thought to result from digestion of plaque proteins by enzymes known as proteases, which weakens plaque structural integrity and leads to rupture. However, this process is poorly understood and is not yet a target of any specific drug therapy. This project aims to unravel the molecular mechanisms through which proteases cause plaque rupture. There are two specific aims: Aim 1 uses blood vessels from genetically modified mice that were developed in our laboratory as an animal model of plaque rupture and Aim 2 uses human plaque tissue. Both aims use powerful new techniques to measure proteins, detect the digestion of proteins, and clarify physiologically meaningful relationships among the proteins. We will use these novel techniques to investigate the pathogenesis of plaque rupture in both the animal model and in human plaque tissue. We hope to identify new molecular targets for therapies that prevent plaque rupture. Moreover, data generated in the two aims will permit an objective assessment of the relevance of the mouse model to human plaque rupture. Therefore, these studies may validate a useful animal model of a common, clinically important, and poorly understood human disease. Accomplishment of our aims will help clarify the mechanisms through which atherosclerotic plaques rupture. Insights from our experiments may be useful in developing new therapies that prevent heart attacks and strokes. PUBLIC HEALTH RELEVANCE: Rupture of atherosclerotic plaques in human arteries is the most common cause of heart attacks and strokes. The biological mechanisms that cause atherosclerotic plaques to rupture are not well understood, and this lack of understanding has hindered the development of therapies that could prevent plaque rupture, heart attacks and strokes. This project aims to identify pathways through which atherosclerotic plaques rupture, with the expectation that this new knowledge will lead to new therapies that prevent heart attacks and strokes.