Leukocyte-Endothelium Interactions in Aging

目前的研究方案将检查随着年龄的增长而发生的血管内皮细胞的表型改变是否通过损害微循环中的白细胞与内皮细胞的相互作用来损害炎症反应的调节机制。病理性白细胞-内皮细胞相互作用与急性和慢性心血管疾病的病理生理学有关，如中风、冠状动脉疾病、心肌梗死和动脉粥样硬化。白细胞与内皮细胞的相互作用在免疫应答、防御传染病和免疫监测中也起着关键作用。老年人心血管疾病的发病率和死亡率较高。由于免疫衰老，老年人的传染病、癌症和自身免疫性疾病的发病率也更高。目前还没有关于衰老对微循环中循环白细胞和内皮细胞之间动态相互作用的影响的数据。为了验证我们的假设，需要解决以下三个与衰老生物学高度相关的问题：1.衰老是否改变了调节微循环中白细胞-内皮相互作用的生理过程？2.衰老是否改变了内皮细胞和循环白细胞上细胞黏附分子的表达？3.衰老是否会导致微循环中的内皮功能障碍，就像在老年动物和人类的大管道动脉中所证明的那样？为了解决上述问题，我们将使用活体显微镜来研究老年大鼠肠系膜微循环中白细胞与内皮细胞的相互作用。我们将研究细胞黏附分子在内皮细胞和循环白细胞上的表达。我们将在活体内检测老龄大鼠微循环中一氧化氮的水平。总体而言，本研究方案旨在为未来更广泛的研究应用提供必要的初步信息，重点是：a)衰老过程中白细胞-内皮相互作用的生理和分子机制，以及b)设计治疗策略以保护老龄生物体的内皮和免疫功能。总体目标是确定衰老的生物标记物，并帮助开发干预策略，以延缓或防止心血管和免疫系统的衰老。

The present research proposal will examine whether that the phenotypic modifications of the vascular endothelium that occur with aging damage the regulatory mechanisms of the inflammatory response by impairing leukocyte-endothelium interaction in the microcirculation. Pathologic leukocyte-endothelium interactions are implicated in the pathophysiology of acute and chronic cardiovascular diseases, such as stroke, coronary artery disease, myocardial infarction, and atherosclerosis. Leukocyte- endothelium interactions also play a key role in the immunologic response, in the defense against infectious diseases, and in the immunosurveillance. The elderly suffer a higher morbidity and mortality from vardiovascu7lar disease. As a result of immuno senescence, the elderly also have higher incidence of infectious diseases, cancer, and autoimmune diseases. Data are not currently available regarding the effect of aging on the dynamic interactions between circulating leukocytes and endothelial cells in the microcirculation. To test our hypothesis, the following three questions highly relevant to the biology of aging need to be addressed: 1. Does aging alter the physiological processes that regulate leukocyte- endothelium interaction in the microcirculation? 2. Does aging change the expression of cell adhesion molecules on endothelial cells and circulating leukocytes? 3. Does aging cause endothelial dysfunction in the microcirculation as it has been demonstrated in large conduit arteries of aged animals and humans? To address the above questions we will use intravital microscopy to study leukocyte-endothelium interactions in the mesenteric microcirculation of aged rats. We will study the expression of cell adhesion molecules on endothelial cells and circulating leukocytes. We will measure levels of nitric oxide in the microcirculation of aged rats in vivo. Overall, the present research proposal is designed to gain the necessary preliminary information for a future more extensive research application focusing on: a) the physiologic and molecular mechanisms of a leukocyte-endothelium interactions in aging and b) the design therapeutic strategies to preserve endothelial and immunologic functions in the aged organism. The overall goal is to identify biological markers of aging and to help developing intervention strategies to delay or prevent senescence of the cardiovascular and immune systems.