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

射血分数保留的心力衰竭中 T 细胞介导的心脏病理学特征机制

• 批准号: 10462140
• 负责人: Sandra Smolgovsky
• 金额: $ 4.23万
• 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: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462140
• 关键词: Binding Proteins; Biological Markers; CD4 Positive T Lymphocytes; Cardiac; Cardiac Myocytes; Cause of Death; Cell Survival; Cells; Characteristics; Chronic; Clinical; Data; Development; Diet; Doctor of Philosophy; Down-Regulation; EFRAC; Elements; Experimental Models; Failure; Functional disorder; Goals; Heart; Heart failure; High Fat Diet; Hospitalization; Hyperlipidemia; Hypertension; Hypertrophy; Immune; Immune response; Immunity; Immunologist; Immunology; Impairment; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Left ventricular structure; Lymphoid Tissue; Mediastinal lymph node group; Mediating; Mus; Myocarditis; Myocardium; NG-Nitroarginine Methyl Ester; Obesity; Pathology; Pathway interactions; Patients; Phenotype; Physiology; Play; Prevalence; Protein Splicing; Proteins; Relaxation; Reporting; Risk Factors; Role; Site; Spleen; Symptoms; Syndrome; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Tumor-infiltrating immune cells; Wild Type Mouse; biomarker development; biomarker identification; cardiometabolism; comorbidity; cytokine; dietary control; effective therapy; effector T cell; endoplasmic reticulum stress; exhaust; exhaustion; improved; in vivo; inhibitor; insight; mortality; mouse model; nitrosative stress; novel; preservation; response; spatiotemporal; systemic inflammatory response; targeted treatment; tumor

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.

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.