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T Lymphopenia in Ischemic Heart Failure

缺血性心力衰竭中的 T 淋巴细胞减少

基本信息

批准号：
10644027
负责人：
Yonggang Ma
金额：
$ 37.87万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644027
关键词：
Acute myocardial infarction Adoptive Transfer Affect American Apoptosis Blood Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CXCR4 gene Cell Count Cell Lineage Cell physiology Chemotaxis Clinical Research Congestive Heart Failure Data Deterioration Diagnosis Glucocorticoid Receptor Glucocorticoids Goals Heart failure Hematopoietic stem cells Impairment Intervention Lymphocyte Count Lymphoid Lymphopenia Lymphopoiesis Mediating Modeling Molecular Morbidity - disease rate Mus Myelopoiesis Myocardial Myocardial Infarction Myocardial Ischemia Outcome PTPRC gene Patients Peripheral Blood Lymphocyte Phenotype Physiological Processes Play Prognosis Proliferating Reperfusion Therapy Risk Role Signal Transduction Stromal Cell-Derived Factor 1 T cell response T memory cell T-Cell Activation T-Cell Development T-Lymphocyte Therapeutic Thymus Gland Travel United States cardiac repair cell type heart damage heart function improved insight interdisciplinary approach mortality novel peripheral blood premature prevent progenitor repaired response side effect stem cells thymocyte tool trafficking wound healing

项目摘要

Myocardial infarction (MI)-induced heart failure is the leading cause of morbidity and mortality in the United States. About one in four MI patients will progress to develop chronic heart failure, which has a 5-year mortality rate of 40%. It is highly urgent to improve long-term outcomes of MI patients. Lymphopenia, a reduction in peripheral blood lymphocyte count (primarily due to T-cell loss), has consistently been shown to correlate with worse cardiac function and poor outcome in MI patients and is an independent marker to predict the prognosis. Unfortunately, how T lymphopenia occurs following MI and whether targeting T lymphopenia has therapeutic potential are largely unknown. Using the mouse MI-induced ischemic heart failure model, our preliminary data showed that MI-induced T lymphopenia may involve blood T-cell redistribution to the bone marrow and T cell development impairment. CD4+ T-cell activation is known to improve wound healing post-MI. Thus, persistent CD4+ T lymphopenia may reduce protective CD4+ T-cell response and compromise myocardial repair after MI. The goals of this proposal are: 1) to elucidate the underlying mechanisms that cause T lymphopenia following MI; and 2) to investigate whether inhibiting CD4+ T lymphopenia can serve as a therapeutic strategy. We hypothesize that MI induces T lymphopenia by both stimulating T-cell trafficking from blood to the bone marrow and impairing T lymphopoiesis; inhibiting CD4+ T lymphopenia improves post-MI cardiac repair. Three specific aims will address this novel hypothesis in a mouse ischemic heart failure model that combines multidisciplinary approaches. Specific Aim 1 will examine the mechanisms of blood T-cell trafficking to the bone marrow and alterations of distinct T-cell phenotypes and functions after MI. Specific Aim 2 will determine the mechanisms by which MI impairs T lymphopoiesis. Specific Aim 3 will examine the hypothesis that inhibiting CD4+ T lymphopenia would improve post-MI cardiac repair. Accomplishment of this proposal will provide new insights into T lymphopenia mechanisms in ischemic heart failure and may offer potential intervention strategies to improve the prognosis of heart failure patients.

心肌梗死（MI）引起的心力衰竭是美国发病率和死亡率的主要原因。 States.大约四分之一的MI患者将发展为慢性心力衰竭，其具有5年死亡率率40%。改善心肌梗死患者的长期预后是当务之急。淋巴细胞减少症，外周血淋巴细胞计数（主要是由于T细胞损失），一直被证明与 MI患者心功能差、预后差，是预测预后的独立指标。不幸的是，MI后T淋巴细胞减少症是如何发生的，靶向T淋巴细胞减少症是否具有治疗作用，潜力在很大程度上未知。利用MI诱导的小鼠缺血性心力衰竭模型，我们的初步数据表明MI诱导的T淋巴细胞减少可能涉及血液T细胞向骨髓和T细胞的再分布，发育障碍已知CD 4 + T细胞活化可改善MI后的伤口愈合。因此， CD 4 + T淋巴细胞减少可能降低保护性CD 4 + T细胞反应，并损害MI后心肌修复。本研究的目的是：1）阐明以下引起T淋巴细胞减少症的潜在机制： MI; 2）研究抑制CD 4 + T淋巴细胞减少症是否可以作为治疗策略。我们假设MI通过刺激T细胞从血液向骨髓的运输诱导T淋巴细胞减少症抑制CD 4 + T淋巴细胞减少改善MI后心脏修复。三个具体 aims将在小鼠缺血性心力衰竭模型中解决这一新的假设，接近。具体目标1将检查血液T细胞运输到骨髓的机制， MI后不同T细胞表型和功能的改变。具体目标2将通过以下方式确定机制： MI损害T淋巴细胞生成。具体目标3将检验抑制CD 4 + T淋巴细胞减少症可以改善心肌梗死后的心脏修复该方案的完成将为T 缺血性心力衰竭中淋巴细胞减少的机制，并可能提供潜在的干预策略，以改善缺血性心力衰竭患者的心功能。心力衰竭患者的预后。