Characterizing mechanisms of T cell-mediated cardiac pathology in Heart Failure with Preserved Ejection Fraction

项目摘要 这项F31建议的目标是研究T细胞对舒张期功能障碍的作用机制 在美国，射血分数保留的心力衰竭(HFpEF)是导致死亡的主要原因，且呈上升趋势 发病率低，直接治疗选择很少，而且无法治愈。我将在完成 量身定做的培训计划，将有助于我作为一名独立的心脏免疫学家的发展，在我完成 我博士学位的要求。HFpEF的特点是左室舒张功能受损， 舒张期功能障碍，心脏收缩能力无明显损害。没有可用的治疗方法 降低HFpEF患者的死亡率，HFpEF患者约占所有HF患者的一半。的一个关键特征 HFpEF是一种全身性慢性低度炎症，也与HFpEF独立相关 肥胖和高血压等并存疾病。而肥胖和高血压都会诱导特定的T细胞 免疫反应，它们不独立地诱导HFpEF，以及它们联合是否诱导特定的T细胞 对HFpEF有贡献的细胞免疫反应仍不清楚。肥胖和高血压加在一起， 产生内质网压力，这种压力不能通过功能失调的未折叠蛋白反应(UPR)来解决。 值得注意的是，UPR蛋白剪接的X盒结合蛋白1(XBP1s)在 在HFpEF患者的心肌中，而在HFrEF患者中不是，提示这一途径可能是 导致了舒张期功能障碍。然而，T细胞免疫在舒张期功能障碍和HFpEF中的作用， 以及普遍定期审议如何调整这一点，仍然难以捉摸。使用最近建立的小鼠模型 肥胖症和高血压合并引起的HFpEF，我的初步数据显示心脏T细胞 伴随着舒张期功能障碍和心肌细胞肥大的细胞浸润。此外，我的数据 表明T细胞缺陷小鼠(TCRA-/-)在以下情况下不会出现舒张期功能障碍或心肌肥大 同样的条件，支持T细胞在HFpEF中的作用。我还发现HFpEF小鼠的T细胞具有 与对照组小鼠的T细胞相比，XBP1s的表达下调。在两个具体的目标中，我将测试 中心假设：HFpEF的联合危险因素诱导T细胞UPR改变，导致增强 T细胞效应器功能和存活，并有助于舒张期功能障碍和心脏代谢性HFpEF。在SA1中， 我将描述HFpEF中T细胞的时空激活，识别主要的T细胞亚群，并定义 T细胞XBP1s和UPR分子在舒张期前后的表达 功能障碍。在SA2中，我将破译XBP1s调节T细胞效应器功能、存活、 心脏代谢性HFpEF的炎性潜伏期。总而言之，这个项目彻底询问了角色 T细胞和T细胞UPR在实验性HFpEF舒张期功能障碍中的作用 在支持我的博士培训的同时，可能的生物标记物和靶点用于治疗干预。

Project Summary The goal of this F31 proposal is to investigate the mechanisms by which T cells contribute to diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF), a leading cause of mortality in the USA, with rising incidence, few direct treatment options, and no cure. I will perform the proposed studies while completing a tailored training plan that will assist in my development as an independent cardio-immunologist, while I complete the requirements of my PhD degree. HFpEF is characterized by impaired relaxation of the left ventricle and diastolic dysfunction, without significant impairment of cardiac contractility. None of the therapeutics available reduce mortality in patients with HFpEF, which comprise about half of all HF patients. A key characteristic of HFpEF is systemic chronic low-grade inflammation, which is also independently associated with HFpEF comorbidities such as obesity and hypertension. While obesity and hypertension each induce specific T cell immune responses, they do not independently induce HFpEF, and whether their combination induces specific T cell immune responses that contribute to HFpEF remains unknown. Obesity and hypertension combined, generate endoplasmic reticulum stress that is unresolved by a dysfunctional unfolded protein response (UPR). Remarkably, a downregulation of the UPR protein spliced X-box binding protein 1 (XBP1s) is observed in the myocardium of HFpEF patients, but not in HFrEF patients, suggesting this pathway may be specific for contributing to diastolic dysfunction. However, the role of T cell immunity in diastolic dysfunction and HFpEF, and how this may be modulated by the UPR, remain elusive. Using a recently established mouse model of HFpEF induced by obesity and hypertension in combination, my preliminary data demonstrate that cardiac T cell infiltration concomitant with diastolic dysfunction and cardiomyocyte hypertrophy occur. Furthermore, my data show that T cell-deficient mice (Tcra-/-) do not develop diastolic dysfunction or cardiomyocyte hypertrophy under the same conditions, supporting a role for T cells in HFpEF. I also found that T cells from HFpEF mice have downregulated XBP1s expression compared to T cells from control mice. In two specific aims, I will test the central hypothesis that combined risk factors of HFpEF induce UPR alterations in T cells that result in enhanced T cell effector function and survival, and contribute to diastolic dysfunction and cardiometabolic HFpEF. In SA1, I will characterize the spatiotemporal activation of T cells in HFpEF, identify dominant T cell subsets, and define the expression of T cell XBP1s and UPR molecules over time, before and during the onset of diastolic dysfunction. In SA2, I will decipher the mechanisms by which XBP1s modulates T cell effector function, survival, and inflammatory potential in cardiometabolic HFpEF. Altogether, this project thoroughly interrogates the roles of T cells and the T cell UPR in diastolic dysfunction in experimental HFpEF and has the potential to identify possible biomarkers and targets for therapeutic intervention while supporting my PhD training.