Comparing the role of MyD88 and TRIF in T-cell effector function and the development of heart failure

比较 MyD88 和 TRIF 在 T 细胞效应功能和心力衰竭发展中的作用

• 批准号: 10733439
• 负责人: Abraham Bayer
• 金额: $ 4.34万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733439
• 关键词: Adaptor Signaling Protein; Adhesions; Adoptive Transfer; Affect; Anti-Inflammatory Agents; Antigen Presentation; Antigens; Binding; Cardiac; Cause of Death; Cell Adhesion; Cell Communication; Cell Death; Cell Survival; Cell physiology; Cells; Chronic; Data; Development; Doctor of Philosophy; Exhibits; Fibroblasts; Fibrosis; Functional disorder; Goals; Heart; Heart Hypertrophy; Heart failure; Helper-Inducer T-Lymphocyte; Immune response; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Integrin alpha4; Interferon Type II; Interferon-beta; Interleukin-2; Investigation; Knock-out; Mediating; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myocarditis; Myofibroblast; Pathway interactions; Patients; Pattern; Persons; Physicians; Prevention; Production; Research Training; Role; Scheme; Scientist; Signal Pathway; Signal Transduction; T cell infiltration; T cell reconstitution; T-Cell Activation; T-Cell Activation Pathway; T-Lymphocyte; TLR4 gene; TNF gene; Testing; Training; United States; Vascular Cell Adhesion Molecule-1; Work; antifibrotic treatment; aorta constriction; career; cell injury; clinical training; coronary fibrosis; effector T cell; heart damage; heart function; improved; in vivo; lymphoid organ; new therapeutic target; novel; receptor; reconstitution; response; restoration; systemic inflammatory response

Project Summary: The goal of this F30 proposal is to characterize novel pathways of T-cell activation that contribute to cardiac fibrosis and systolic dysfunction in heart failure (HF), and simultaneously train to be a successful physician scientist. HF is a leading cause of death worldwide, and consists of irreversible cardiac fibrosis, progressive loss of cardiac function, and cardiac inflammation. While both local and systemic inflammation have been observed in patients with HF, no anti-inflammatory therapies have successfully been used in HF, highlighting the need for a deeper mechanistic study of the cardiac inflammatory response. Damage associated molecular patterns (DAMPs) signal myeloid cells to promote antigen presentation to T-cells, which infiltrate the heart and participate in cardiac fibrosis and hypertrophy. DAMP signaling converges on two adaptor proteins: Myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adaptor inducing interferon-β (TRIF), which initiate both independent and overlapping pro-inflammatory pathways. MyD88 and TRIF, along with DAMP receptors, are also expressed in T-cells, implying T-cell DAMP sensing can impact T-cell activation in an antigen-independent manner, termed “bystander activation.” However, the significance of bystander T-cell activation in HF and mechanisms involved remain largely unexplored. My lab has shown that reconstitution of T-cell deficient mice (Tcra-/-), normally protected from HF induced by transverse aortic constriction (TAC), with type I helper T-cells (Th1) in the onset of TAC partially restores cardiac fibrosis. Mechanistically, this is dependent on Th1 cell adhesion to and activation of cardiac fibroblasts. I surprisingly found that reconstitution of Tcra-/- mice with Myd88-/- Th1 cells resulted in significantly higher numbers of cardiac T-cells and enhanced cardiac fibrosis than WT Th1 cells. I also found that Myd88-/- and Trif-/- Th1 cells showed opposite effects on T-cell effector functions and survival. In two specific aims, I will test the central hypothesis that DAMP signaling through MyD88 and TRIF differentially regulates T-cell effector functions and contributes to cardiac fibrosis and systolic dysfunction in HF. In SA1 I will investigate whether signaling through MyD88 and TRIF differentially contributes to T-cell activation and cell survival and the mechanisms involved. In SA2 I will characterize the contribution of T-cell MyD88 and TRIF to cardiac fibrosis and systolic dysfunction in experimental HF in vivo, and the specific mechanisms of cardiac fibroblast activation in vitro. Successful completion of these aims will uncover novel mechanisms of T-cell mediated cardiac fibrosis in HF, while supporting a tailored training plan that integrates clinical and research training to prepare me for a career as an independent physician scientist.

项目概要： F30 提案的目标是描述 T 细胞激活的新途径，这些途径有助于 心脏纤维化和心力衰竭（HF）收缩功能障碍，同时训练成为一名成功的 医师科学家。心力衰竭是全世界死亡的主要原因，由不可逆的心脏纤维化、 心脏功能进行性丧失和心脏炎症。虽然局部和全身炎症都有 在心力衰竭患者中观察到，尚未成功使用抗炎疗法治疗心力衰竭， 强调需要对心脏炎症反应进行更深入的机制研究。相关损坏 分子模式 (DAMP) 向骨髓细胞发出信号，促进抗原呈递给 T 细胞，T 细胞会渗透到 心脏并参与心脏纤维化和肥厚。 DAMP 信号传导集中在两个接头蛋白上： 骨髓分化初级反应 88 (MyD88) 和含有 TIR 结构域的接头诱导干扰素-β （TRIF），启动独立和重叠的促炎途径。 MyD88 和 TRIF 以及 与 DAMP 受体一起，也在 T 细胞中表达，这意味着 T 细胞 DAMP 感应可以影响 T 细胞激活 以一种不依赖于抗原的方式，称为“旁观者激活”。然而，旁观者 T 细胞的重要性 心力衰竭的激活及其相关机制在很大程度上仍未被探索。我的实验室表明重构 T 细胞缺陷小鼠 (Tcra-/-)，通常可免受横主动脉缩窄 (TAC) 诱导的心力衰竭的影响， TAC 发作时 I 型辅助 T 细胞 (Th1) 可部分恢复心脏纤维化。从机制上讲，这是依赖的 Th1 细胞粘附和心肌成纤维细胞活化的影响。我惊讶地发现 Tcra-/- 小鼠的重构 Myd88-/- Th1 细胞导致心脏 T 细胞数量显着增加并增强心脏纤维化 比 WT Th1 细胞。我还发现 Myd88-/- 和 Trif-/- Th1 细胞对 T 细胞效应器表现出相反的作用 功能和生存。在两个具体目标中，我将测试中心假设，即 DAMP 信号通过 MyD88 TRIF 差异性调节 T 细胞效应功能并导致心脏纤维化和收缩 HF 功能障碍。在 SA1 中，我将研究通过 MyD88 和 TRIF 发出的信号是否有不同的贡献 T 细胞激活和细胞存活及其相关机制。在 SA2 中，我将描述以下贡献： T细胞MyD88和TRIF对体内实验性心力衰竭心脏纤维化和收缩功能障碍的影响，以及具体作用 心脏成纤维细胞体外激活机制。成功完成这些目标将发现新的 T 细胞介导的心力衰竭心脏纤维化机制，同时支持定制的培训计划，该计划整合了 临床和研究培训，为我成为一名独立医师科学家的职业生涯做好准备。