Pathological TNFR1 Expressing CD4+ T-cells are Critical for HF progression

病理性表达 TNFR1 的 CD4 T 细胞对于心力衰竭进展至关重要

• 批准号: 9768529
• 负责人: Shyam Sunder Bansal
• 金额: $ 24.64万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768529
• 关键词: Ablation; Academia; Academic Training; Acute; Adoptive Transfer; Antibodies; Antigen-Presenting Cells; Apoptosis; Award; Basic Science; Biochemistry; Blood; Blood Circulation; Blood capillaries; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular biology; Chronic; Chronic Phase; Circadian Rhythms; Clinic; Clinical; Clinical Research; Clinical Trials; Clonal Expansion; Collaborations; Complex; Congestive Heart Failure; Core Facility; Coronary; Data; Dendritic Cells; Development; Development Plans; Discipline; Disease; Disease Progression; Dissection; Doctor of Philosophy; Drug Delivery Systems; Drug Kinetics; Echocardiography; Educational workshop; Environment; Equipment; Event; Faculty; Fibrosis; Flow Cytometry; Foundations; Functional disorder; Goals; Grant; Heart; Heart failure; Hindlimb; Human; Hypertrophy; Image; Immune; Immune response; Immunohistochemistry; Industry; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Laboratories; Left Ventricular Remodeling; Ligation; Lymphocyte Count; Manuscripts; Mediastinal lymph node group; Mediating; Mediator of activation protein; Mentors; Methodology; Molecular Biology; Mus; Muscle; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocarditis; Myocardium; Nuclear; PTPRC gene; Paper; Pathogenesis; Pathologic; Pathology; Patients; Pharmacology and Toxicology; Phase; Phenotype; Physiology; Plasma; Play; Positioning Attribute; Prognostic Marker; Proliferating; Publishing; Rag1 Mouse; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Research Proposals; Resources; Role; Scientist; Secure; Severities; Signal Transduction; Signaling Molecule; Spleen; Systolic heart failure; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; TNFRSF1A gene; Techniques; Testing; Therapeutic; Tissues; Training; Transgenic Mice; Transgenic Organisms; Work; Writing; base; cardiac repair; career; career development; cell type; cellular targeting; cytokine; diphtheria toxin receptor; effector T cell; healing; heart function; heart metabolism; immunoreaction; immunoregulation; improved; indexing; lymph nodes; macrophage; meetings; monocyte; mouse model; multidisciplinary; neovascularization; new therapeutic target; novel; novel strategies; novel therapeutic intervention; p65; pressure; programs; promoter; receptor; repository; response; skills; spatiotemporal; tenure track; trafficking; translational approach

 DESCRIPTION (provided by applicant):Project Summary Candidate. My long term goal is to secure a tenure track faculty position as an independent investigator in translational cardiovascular research. To achieve this aim, I have devised a multi-faceted career development plan with several strategic short term goals that include i) advanced academic training through upper graduate level courses, ii) develop my writing skills by participating in grant and manuscript related workshops, iii) networking for collaborative research, iv) attend and present at national meetings, and v) work to publish high impact papers. I intend to participate in these activities during the K99 phase so that I can effectively transition to the R0 phase to independently develop and manage my own research program and research proposals to submit independent grants. My training in basic science will focus on acquiring abilities to carry out advanced techniques in the study of integrative cardiac physiology (echocardiography and pressure-volume) and T-cell signaling mechanisms (TNF-TNFR1 axis) with the aim to ultimately integrate these diverse fields to establish a distinct and novel researc paradigm which will lay the foundation for my independent academic career. In the long term, I envision incorporating my multi-disciplinary training in drug delivery, pharmacology, toxicology, pharmacokinetics and cardiovascular diseases to understand pathophysiology of heart failure and devise novel translational strategies. With my unique background and support from this award, I aim to develop effective collaborations between academia and industry to successfully transition my research findings to the clinic. Environment. To support my long term career goals, I have included world renowned clinician scientists; Dr. Sumanth D. Prabhu, MD, and Dr. Louis J. Dell'Italia, MD, actively working in heart failure; Dr. Casey T Weaver, MD, expert in T-cell biology and Dr. Martin E. Young, PhD, expert in cardiac metabolism/circadian rhythms, in my mentoring team. This multi-disciplinary combination of investigators provides me an excellent and unique training environment conducive to creating a successful translational cardiovascular investigator. Dr. Prabhu and Dr. Weaver's laboratories are well equipped with all the resources, equipment, and methodologies required for successful execution of proposed studies. The Comprehensive Cardiovascular Center (CCVC) at UAB consists of several clinician scientists and basic research investigators with expertise in diverse disciplines including physiology, pathology, molecular biology, biochemistry, and imaging. This multidimensional research environment will significantly facilitate my development as an academic scientist and as a mentor. This excellent research environment, cutting edge core facilities available through UAB will provide crucial support for the successful completion of this proposal and my training. Research. Chronic inflammatory and immune responses are an integral part of post-infarct heart failure (HF) and dictate subsequent infarct healing and left ventricular (LV) remodeling. The identification of augmented levels of several pro-inflammatory cytokines resulted in therapeutic efforts directed toward their neutralization, which failed in clinical studies. The fact that increased cytokine levels is not the proximate cause of underlying pathology but is the result of activated inflammatory responses emphasizes a more complex role of inflammatory and immune reactions in cardiac repair after myocardial infarction (MI). In this regard, recent studies with CD4-/- mice indicated that during the acute phase CD4+ T-cells play a crucial role in the healing of ischemic hearts and hind-limb muscles by promoting neovascularization and reducing fibrotic tissue formation. However, global knockout mouse models (such as CD4-/-) fail to consider spatio-temporal alterations as we see during progression from acute to chronic HF. Nonetheless, the clinical correlates that can demonstrate the role of CD4+ T-cells during chronic HF are not known. During persistent tissue injury such as in HF, innate immune cells act as antigen presenting cells to activate differentiation and clonal expansion of effector T-cells and long lasting memory T-cells. Intense activation of monocytes and macrophages during the acute phase thus implies activation of T-cells also. Indeed, our preliminary results clearly show heightened activation and expansion of T-cells in the ischemic myocardium, circulation, and remodeled spleen during chronic HF. Our preliminary results also suggest global spatio-temporal alterations in T-cell phenotype, mediated by enhanced expression of TNFα and TNFR1, classical pro-inflammatory signaling molecules that have been shown to correlate with HF severity and cardiac dysfunction clinically. This, therefore, implies that T-cells exert a complex biphasic effect in the ischemic heart leading us to hypothesize that a pro-inflammatory phenotypic switch to TNFR1 expression during chronic HF pathologically alters CD4+ T-cells to promote cardiac tissue injury and pathological LV remodeling, and HF disease progression. Importantly, these are key cellular targets for immunomodulation. We will test this hypothesis by i) delineating global CD4+ T-cell trafficking and pro-inflammatory phenotype in HF, ii) establishing the pathophysiologic role of CD4+ T-cells in LV remodeling and chronic HF by reversibly and specifically ablating pathological T-cells in transgenic CD4-DTR mice, and iii) defining whether TNFR1+ CD4+ T-cells are both necessary and sufficient for adverse LV remodeling in chronic HF by adoptive transfer studies of TNFR1+or TNFR1- CD4+ T-cells.

 描述（由申请人提供）：项目摘要候选人。我的长期目标是获得转化心血管研究的独立研究员的终身教授职位。为了实现这一目标，我制定了一个包含多项战略的多方面职业发展计划。短期目标包括 i) 通过研究生高年级课程进行高级学术培训，ii) 通过参加资助和手稿相关研讨会来提高我的写作技能，iii) 合作研究网络，iv) 参加并出席全国会议，以及 v)工作到我打算在 K99 阶段参与这些活动，以便能够有效地过渡到 R0 阶段，以独立开发和管理自己的研究计划和研究提案，以提交独立的资助。我将重点关注基础科学方面的培训。获得在综合心脏生理学（超声心动图和压力容积）和 T 细胞信号传导机制（TNF-TNFR1 轴）研究中开展先进技术的能力，旨在最终整合这些不同的领域，建立独特而新颖的研究范式从长远来看，我设想将我在药物输送、药理学、毒理学、药代动力学和心血管疾病方面的多学科培训结合起来，以了解心力衰竭的病理生理学，并以我独特的方式设计新颖的转化策略。在该奖项的背景和支持下，我的目标是在学术界和工业界之间建立有效的合作，以成功地将我的研究成果转化为临床环境，以支持我的长期职业目标，我邀请了世界著名的临床科学家； Prabhu 医学博士和 Louis J. Dell'Italia 医学博士积极致力于心力衰竭领域的研究；Casey T Weaver 医学博士（T 细胞生物学专家）和 Martin E. Young 博士（心脏代谢专家） /昼夜节律，在我的指导团队中，这种多学科的研究人员组合为我提供了一个优秀而独特的培训环境，有利于培养一名成功的转化心血管研究人员。 Prabhu 博士和 Weaver 博士的实验室配备了所有资源，阿拉巴马大学综合心血管中心 (CCVC) 拥有成功执行拟议研究所需的设备和方法，由多名临床科学家和基础研究人员组成，他们拥有生理学、病理学、分子生物学、生物化学和影像学等多个学科的专业知识。研究环境将极大地促进我作为一名学术科学家和导师的发展。UAB 提供的一流研究环境和尖端核心设施将为我的慢性炎症和免疫研究的成功完成提供重要支持。反应是梗塞后心力衰竭（HF）的一个组成部分，并决定随后的梗塞愈合和左心室（LV）重塑。对几种促炎细胞因子水平升高的识别导致了针对其中和的治疗努力，但失败了。临床研究表明，细胞因子水平升高并不是潜在病理的直接原因，而是炎症反应激活的结果，这一事实强调了炎症和免疫反应在心肌梗死（MI）后心脏修复中的更复杂的作用。考虑到，最近的研究 CD4-/-小鼠的研究表明，在急性期，CD4+ T细胞通过促进新血管形成和减少纤维化组织形成，在缺血性心脏和后肢肌肉的愈合中发挥着至关重要的作用。 -/-) 未能考虑我们在急性心力衰竭进展过程中所看到的时空变化。然而，可以证明 CD4+ T 细胞在慢性心力衰竭期间的作用的临床相关性并不存在。众所周知，在持续性组织损伤（例如心力衰竭）期间，先天免疫细胞充当抗原呈递细胞，激活效应 T 细胞和持久记忆 T 细胞的分化和克隆扩增，这意味着单核细胞和巨噬细胞在急性期会被强烈激活。事实上，我们的初步结果清楚地表明慢性心力衰竭期间缺血心肌、循环和重塑的脾脏中 T 细胞的氧激活和扩张。 T 细胞表型的时空变化是由 TNFα 和 TNFR1 表达增强介导的，这两种经典促炎信号分子已被证明与临床心力衰竭严重程度和心脏功能障碍相关。缺血性心脏中复杂的双相效应使我们认为慢性心力衰竭期间促炎表型向 TNFR1 表达的转变会病理改变 CD4+ T 细胞，从而促进心脏组织损伤和重要的是，这些是免疫调节的关键细胞靶点，我们将通过 i) 描述 HF 中的整体 CD4+ T 细胞运输和促炎表型，ii) 确定 CD4+ 的病理生理作用来检验这一假设。通过可逆性和特异性消融转基因 CD4-DTR 小鼠中的病理性 T 细胞来研究左室重塑和慢性心力衰竭中的 T 细胞，以及 iii) 确定 TNFR1+ 是否通过 TNFR1+ 或 TNFR1- CD4+ T 细胞的过继转移研究，CD4+ T 细胞对于慢性心力衰竭的不良 LV 重塑既是必要的也是充分的。