Role of T cells in Uremic Cardiomyopathy

摘要 指导临床科学家研究事业奖(K08)的修订提案中概述的工作 将为候选人提供必要的培训和指导，使其成为一名独立的 慢性肾脏病的免疫学后果的研究人员和专家，特别是与心血管相关的 合并症。心血管疾病是近2000万美国人的主要死亡原因 患有慢性肾脏病(CKD)。以左室肥厚为特征的尿毒症心肌病 左心室肥厚和舒张期功能不全可预测慢性肾脏病患者的死亡率。潜在的机制 导致尿毒症心肌病发展的因素尚不完全清楚，限制了治疗 选择。文献表明，在慢性肾脏病过程中，促炎T细胞的积聚增加了 心血管疾病通过未知的机制，使我们进一步探索T细胞在尿毒症中的作用 心肌病。我们有令人兴奋的初步数据表明T细胞是病理的基础 慢性肾脏病实验性模型的心脏改变。我们最重要的假设是T细胞被 尿毒症是慢性肾脏病心脏重构的重要因素。 这项建议中的科学方法利用了导致尿毒症的慢性肾脏病小鼠模型。 心肌病(左心室肥厚和舒张期功能障碍)和促炎性T细胞积聚。首先，我们将 确定两个主要T细胞亚群(CD4+和CD8+)在尿毒症发病机制中的不同作用 心肌病。下一步，我们建议询问携带共抑制受体PD-1或 KLRG1在尿毒症心肌病过继转移研究中的作用及PD-1信号转导的必要性 体内使用抗体阻断的途径。最后，我们将研究共同刺激的贡献。 OX40途径，包括它如何与慢性肾脏病时T细胞中KLRG1和PD-1的上调有关。这 这项工作将为T细胞在尿毒症心肌病中的作用提供重要的机制洞察，为 慢性肾脏病患者的新治疗策略之路。 我们已经组建了一支由美国国立卫生研究院资助的导师团队，他们拥有不同的和互补的专业知识来支持 候选人在三个科学领域的发展：免疫学、心血管生物学和慢性病 肾脏疾病。职业发展计划的结构是为了扩大免疫学知识，硕士 先进的免疫学实验方法，进一步发展实验方法技能 心血管生物学，在科学交流方面的成熟技能，并为能够翻译 未来的基础科学发现。这位候选人的主要导师曼迪·福特博士是一位典型的- 训练有素的免疫学家，具有T细胞记忆发育和共刺激信号方面的专业知识。阿山博士 侯赛因作为共同导师，将提供心血管生物学方面的专业知识，拉里·格林鲍姆博士将帮助我 在形成关系和未来翻译研究的项目想法方面。

Abstract The work outlined in this revised proposal for the Mentored Clinical Scientist Research Career Award (K08) will provide the training and mentorship necessary for the candidate to develop into an independent investigator and expert in the immunological consequences of CKD, specifically in relation to cardiovascular comorbidities. Cardiovascular disease is the leading cause of death for the nearly 20 million Americans living with chronic kidney disease (CKD). Uremic cardiomyopathy, characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction, predicts mortality among patients with CKD. The underlying mechanisms contributing to the development of uremic cardiomyopathy are incompletely understood, limiting treatment options. The literature suggests that the accumulation of pro-inflammatory T cells during CKD confer risk for cardiovascular disease via unknown mechanisms, leading us to further explore a role for T cells in uremic cardiomyopathy. We have exciting preliminary data suggesting T cells mechanistically underlie the pathological cardiac changes in an experimental model of CKD. Our overarching hypothesis is that T cells altered by uremia contribute to cardiac remodeling during CKD. The scientific approach in this proposal utilizes a murine model of CKD that results in uremic cardiomyopathy (LVH and diastolic dysfunction) and accumulation of pro-inflammatory T cells. First, we will identify the differential role of the two major subsets of T cells (CD4+ and CD8+) in the pathogenesis of uremic cardiomyopathy. Next, we propose interrogating the role of T cells bearing the co-inhibitory receptors, PD-1 or KLRG1, in uremic cardiomyopathy via adoptive transfer studies and the necessity of the PD-1 signaling pathway using antibody blockade in vivo. Finally, we will investigate the contribution of the co-stimulatory pathway, OX40, including how it relates to the up-regulation of KLRG1 and PD-1 in T cells during CKD. This work will provide important mechanistic insight into the role of T cells during uremic cardiomyopathy, paving the way for novel therapeutic strategies in patients with CKD. We have assembled of a team of NIH-funded mentors with diverse and complementary expertise to support the candidate’s development in three scientific domains: immunology, cardiovascular biology, and chronic kidney disease. The career development plan is structured to expand knowledge in immunology, master advanced experimental methods in immunology, further develop skills in experimental methods in cardiovascular biology, mature skills in scientific communication, and lay a foundation to enable translation of basic science discoveries in the future. The candidate’s primary mentor, Dr. Mandy Ford, is a classically- trained immunologist with expertise in T cell memory development and costimulatory signaling. Dr. Ahsan Husain, as co-mentor, will provide expertise in cardiovascular biology, and Dr. Larry Greenbaum will assist me in forming relationships and project ideas for future translational studies.