Role of T cells in Uremic Cardiomyopathy

T 细胞在尿毒症心肌病中的作用

• 批准号: 10471526
• 负责人: Pamela D Winterberg
• 金额: $ 10.78万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471526
• 关键词: Address; Adoptive Transfer; Affect; Age; American; Antibodies; Antigens; Award; Basic Science; Biology; Blocking Antibodies; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiac; Cardiac health; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cessation of life; Child; Child Care; Childhood; Chronic Kidney Failure; Clinical; Communication; Complex; Cytotoxic T-Lymphocytes; Data; Development; Development Plans; Disease model; Event; Experimental Models; Foundations; Functional disorder; Funding; Future; Heart; Heart failure; Helper-Inducer T-Lymphocyte; Hypertension; Immune; Immunologics; Immunologist; Immunology; In Vitro; Inflammation; Inflammatory; Interferon Type II; Interleukin-2; K-Series Research Career Programs; Knowledge; Left Ventricular Hypertrophy; Literature; Medical; Mentors; Mentorship; Methods; Morbidity - disease rate; Mus; Myocardial; Nephrology; OX40; OX40 Signaling Pathway; PD-1 pathway; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Population; Production; Publishing; Renal function; Reporting; Research; Research Personnel; Role; Scientist; Severities; Signal Transduction; Structure; T memory cell; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; TNFSF4 gene; Thick; Training; Translations; United States National Institutes of Health; Up-Regulation; Uremia; Work; cardiovascular disorder risk; cardiovascular risk factor; career; career development; comorbidity; coronary fibrosis; cytokine; heart function; improved; in vivo; insight; mortality; mortality risk; mouse model; novel therapeutic intervention; prevent; programmed cell death protein 1; receptor; skills; targeted treatment; translational study; uremic cardiomyopathy

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. !

摘要 ! 本修订提案中概述的指导临床科学家研究职业奖（K 08）的工作 将为候选人提供必要的培训和指导，以发展成为一个独立的 CKD免疫学后果的研究者和专家，特别是与心血管疾病相关的免疫学后果 合并症。心血管疾病是近2000万美国人死亡的主要原因， 慢性肾脏病（CKD）尿毒症心肌病，以左心室肥大为特征 (LVH)和舒张功能障碍，预测CKD患者的死亡率。潜在的机制 导致尿毒症性心肌病发展的原因尚不完全清楚，限制了治疗 选项.文献表明，CKD期间促炎性T细胞的积累会增加CKD的风险。 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细胞是病理性 CKD实验模型中的心脏变化。我们的首要假设是，T细胞被 尿毒症有助于CKD期间的心脏重构。 该提案中的科学方法利用了导致尿毒症的CKD小鼠模型， 心肌病（LVH和舒张功能障碍）和促炎性T细胞的积累。一是 确定T细胞的两个主要亚群（CD 4+和CD 8+）在尿毒症发病机制中的不同作用， 心肌病接下来，我们提出询问携带共抑制受体PD-1或PD-2的T细胞的作用。 KLRG 1在尿毒症心肌病中的过继转移研究和PD-1信号传导的必要性 在体内使用抗体阻断途径。最后，我们将研究共刺激因子的贡献。 OX 40通路，包括它如何与CKD期间T细胞中KLRG 1和PD-1的上调相关。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见解， CKD患者的新治疗策略的途径。 我们已经组建了一个由NIH资助的导师团队，他们具有多样化和互补的专业知识， 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 肾病职业发展计划的结构，以扩大免疫学知识，硕士 先进的免疫学实验方法，进一步发展实验方法的技能， 心血管生物学，成熟的科学交流技能，并奠定基础，使翻译 未来的基础科学发现。候选人的主要导师，曼迪福特博士，是一个典型的- 训练有素的免疫学家，在T细胞记忆发育和共刺激信号传导方面具有专业知识。Ahsan博士 Husain作为共同导师，将提供心血管生物学方面的专业知识，Larry Greenbaum博士将协助我 在形成关系和项目的想法，为未来的翻译研究。 !