T-cell Co-stimulation in Obesity-induced Inflammation and Atherosclerosis

描述(由申请人提供)：肥胖是动脉粥样硬化和肥胖相关代谢紊乱的潜在危险因素。炎症被认为是这两个过程的关键。我们试图了解T细胞、适应性免疫系统在这些炎症过程中的作用。在动脉粥样硬化方面，已经在人类动脉粥样硬化斑块中发现了活化的T细胞。我们计划通过抑制两种不同的T细胞共刺激途径来干扰它们的激活，从而评估T细胞激活在脂肪组织和动脉壁炎中的作用。T细胞的激活分两步进行，首先是T细胞受体-抗原识别，然后是CD80/86-CD28途径的激活。其他可能具有协同作用的共刺激途径包括CD40-CD40L途径。T细胞的激活高度依赖于这些途径的共同刺激作用。CD80/86-CD28通路可被FDA批准的生物制剂CTLA-4 Ig或abatacept抑制。CD40配体中和抗体(CD40L)可抑制CD40-CD40L途径。尽管用抗CD40L抗体阻断CD40/CD40L通路可以改善动脉粥样硬化，但CTLA-4Ig单独或联合抗CD40L抗体对动脉粥样硬化的影响尚未被研究。由于CTLA-4Ig和抗CD40L抗体的结合是一种在适应性免疫反应中诱导耐受的有效方法，因此在肥胖相关的炎症和动脉粥样硬化的背景下测试这一组合是很重要的。这项建议的目的是评估这些药物单独和联合使用在小鼠脂肪组织炎症和动脉粥样硬化发展中的效果。我们计划在C57BL/6背景下使用低密度脂蛋白受体基因敲除(Ldlr-/-)小鼠。当这些小鼠的饮食与典型的西方饮食相似，即高饱和脂肪和高胆固醇时，这些小鼠容易发生脂肪组织炎症、胰岛素抵抗和动脉粥样硬化病变。此外，我们计划评估以下项目的效果 脂肪酸和高密度脂蛋白在体外对T细胞增殖的影响，这可能导致识别这些分子调节适应性免疫反应的机制。此外，我们的初步体外数据表明，前脂肪细胞具有独特的特性，可以产生专业抗原呈递所需的分子。我们将扩大这些研究，以确认和确定这一发现的意义。阐明可以缓解脂肪组织炎症、胰岛素抵抗和动脉粥样硬化发展的重要途径和制剂，可能会导致对人类这些情况的进一步干预。这些项目将是一个结构化的有指导的职业发展计划的一部分，最终我将成为一名独立的研究员，成为一名内科科学家。我的导师和共同导师制定了一个计划，以确保我在这个机会的指定时间框架内实现我的目标。华盛顿大学的研究环境对于一个崭露头角的内科科学家来说是非常好的，我计划绝对利用可用的资源。(摘要结束)

DESCRIPTION (provided by applicant): Obesity is an underlying risk factor for atherosclerosis and obesity-associated metabolic disorders. Inflammation has been linked as a key to both these processes. We seek to understand the role of T cells, of the adaptive immune system in these inflammatory processes. With respect to atherosclerosis, activated T cells have been found in human atherosclerotic plaques. We plan to evaluate the role of T cell activation in both adipose tissue and arterial wall inflammation by interfering with their activation by inhibiting tw distinct pathways of T cell co-stimulation. T cells are activated in a two-step process, initially involving T cell receptor- antigen recognition, and then activation of the CD80/86-CD28 pathway. Other co-stimulatory pathways that may be synergistic include the CD40-CD40L pathway. T cell activation is highly dependent on the co- stimulatory actions of these pathways. The CD80/86-CD28 pathway can be inhibited by CTLA-4 Ig, or abatacept, an FDA- approved biologic agent. The CD40-CD40L pathway can be inhibited by a neutralizing antibody to CD40 ligand (CD40L). Although blocking the CD40/CD40L pathway with an anti-CD40L antibody has been shown to ameliorate atherosclerosis, the effects of CTLA-4 Ig alone and in conjunction with anti- CD40L antibody on atherosclerosis have not been studied. Since the combination of CTLA-4 Ig and anti- CD40L antibody is a validated method of inducing tolerance in adaptive immune responses, it is important to test this combination in the setting of obesity-associated inflammation and atherosclerosis. The goal of this proposal is to evaluate the effects of these agents alone and in combination in the development of adipose tissue inflammation and atherosclerosis in mice. We plan on using LDL receptor knockout (Ldlr-/-) mice on the C57BL/6 background. These mice are susceptible to adipose tissue inflammation, insulin resistance and atherosclerotic lesion development when placed on a diet that resembles the typical Western diet that is high in saturated fat and cholesterol. In addition, we plan to evaluate the effects of fatty acids and HDL on T cell proliferation in vitro, which can lead to identification of mechanisms of adaptive immune response modulation by these molecules. Also, our preliminary in vitro data suggest a unique property of pre-adipocytes to develop molecules required for professional antigen presentation. We will expand these studies to confirm and identify the significance of this finding. Elucidating important pathways and agents that can mitigate the development of adipose tissue inflammation, insulin resistance and atherosclerosis may lead to further interventions for these conditions in humans. These projects will be part of a structured mentored career development program that will culminate in my becoming an independent investigator as a physician-scientist. My mentor and co- mentors have developed a plan to ensure that I attain my goals within the specified time frame of this opportunity. The research environment at the University of Washington is excellent for a budding physician- scientist, and I plan on taking absolute advantage of the resources available. (End of Abstract)