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。尽管在医疗和外科治疗方面取得了重大进展，动脉粥样硬化仍然导致显著的发病率和死亡率。由于人口老龄化和目前年轻人中肥胖/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），动脉粥样硬化对美国人健康的影响预计将在未来几十年增加。该项目的长远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。动脉粥样硬化导致血管狭窄，限制血液流动，导致胸部和腿部疼痛，并限制身体活动。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——主要是由动脉粥样硬化斑块的物理破坏或“破裂”引起的，随后形成的血栓要么完全阻塞血管，要么游离并阻塞斑块破裂部位下游的血管。斑块破裂被认为是由于被称为蛋白酶的酶消化斑块蛋白质，从而削弱斑块结构完整性并导致破裂。然而，人们对这一过程了解甚少，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酶导致斑块破裂的分子机制。有两个特定的目的：Aim 1使用我们实验室开发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，并阐明蛋白质之间有意义的生理关系。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。我们希望找到新的分子靶点来预防斑块破裂。此外，在两个目标中产生的数据将允许客观评估小鼠模型与人类斑块破裂的相关性。因此，这些研究可能验证了一种常见的、临床上重要的、人们知之甚少的人类疾病的有用动物模型。完成我们的目标将有助于阐明动脉粥样硬化斑块破裂的机制。从我们的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。

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.