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: 10534476
• 负责人: Abraham Bayer
• 金额: $ 4.25万
• 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/10534476
• 关键词: Adaptor Signaling Protein; Adhesions; Adoptive Transfer; Affect; Anti-Inflammatory Agents; Antigen Presentation; Antigens; Binding; Cardiac; Cardiac development; Cause of Death; Cell Adhesion; Cell Communication; Cell Death; Cell Survival; Cell physiology; Cells; Chronic; Clinical Research; 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 reconstitution; T-Cell Activation; T-Cell Activation Pathway; T-Lymphocyte; TLR4 gene; TNF gene; Testing; Training; Tumor-infiltrating immune cells; United States; Vascular Cell Adhesion Molecule-1; Work; antifibrotic treatment; base; cardiogenesis; career; cell injury; constriction; 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.

项目摘要： 这个F30提案的目标是表征T细胞活化的新途径， 心脏纤维化和心脏收缩功能障碍的心力衰竭（HF），并同时训练成为一个成功的 医学科学家HF是全世界死亡的主要原因，并且包括不可逆的心脏纤维化， 进行性心脏功能丧失和心脏炎症。虽然局部和全身炎症都有 在HF患者中观察到，没有抗炎疗法成功地用于HF， 强调需要对心脏炎症反应进行更深入的机制研究。损伤相关 分子模式（DAMP）信号髓样细胞促进抗原呈递给T细胞，T细胞浸润 参与心脏纤维化和肥大。DAMP信号传导集中在两个衔接蛋白上： MyD 88和含TIR结构域的接头诱导β-干扰素 （TRIF），其启动独立和重叠的促炎途径。MyD 88和TRIF，沿着 与DAMP受体一起，也在T细胞中表达，这意味着T细胞DAMP传感可以影响T细胞活化 称为“旁观者激活”。然而，旁观者T细胞 HF中的激活和所涉及的机制仍然在很大程度上未被探索。我的实验室已经证明 T细胞缺陷型小鼠（Tcra-/-），正常情况下可免于由横向主动脉缩窄（TAC）诱导的HF， TAC发作时的I型辅助T细胞（Th 1）部分恢复心脏纤维化。从机制上讲，这是依赖于 Th 1细胞粘附和激活心脏成纤维细胞。我惊奇地发现重组Tcra-/-小鼠 Myd 88-/-Th 1细胞导致心脏T细胞数量显著增加，心脏纤维化增强 WT Th 1细胞。我还发现Myd 88-/-和Trif-/-Th 1细胞对T细胞效应细胞的作用相反， 功能与生存在两个具体的目标，我将测试中心假设，DAMP信号通过MyD 88 和TRIF差异调节T细胞效应功能，并有助于心脏纤维化和收缩压 HF中的功能障碍。在SA 1中，我将研究通过MyD 88和TRIF的信号传导是否有差异 T细胞激活和细胞存活及其相关机制。在SA 2中，我将描述 T细胞MyD 88和TRIF对实验性HF心脏纤维化和收缩功能障碍的影响， 体外心脏成纤维细胞活化的机制。成功完成这些目标将揭示新的 HF中T细胞介导的心脏纤维化的机制，同时支持定制的训练计划， 临床和研究培训，为我作为一个独立的医生科学家的职业生涯做好准备。