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终身教职，成为心血管转化研究的独立研究者。为了实现这一目标，我设计了一个多方面的职业发展计划，其中包括几个战略性的短期目标，i）通过高级研究生课程进行高级学术培训，ii）通过参加赠款和手稿相关研讨会来发展我的写作技能，iii）合作研究的网络，iv）出席并出席国家会议，v）努力发表高影响力的论文。我打算在K99阶段参与这些活动，以便我能够有效地过渡到R0阶段，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。我在基础科学方面的培训将侧重于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，目的是最终整合这些不同的领域，建立一个独特而新颖的研究范式，这将为我的独立学术生涯奠定基础。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设计新的转化策略。凭借我独特的背景和该奖项的支持，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。环境为了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;凯西T韦弗医学博士，T细胞生物学专家和马丁E。Young，博士，心脏代谢/昼夜节律专家，我的导师团队。这种多学科的研究者组合为我提供了一个优秀的和独特的培训环境，有利于创造一个成功的翻译心血管研究者。Prabhu博士和Weaver博士的实验室配备了成功执行拟议研究所需的所有资源、设备和方法。UAB的综合心血管中心（CCVC）由多名临床科学家和基础研究调查人员组成，他们具有生理学、病理学、分子生物学、生物化学和成像等多个学科的专业知识。这种多维的研究环境将大大促进我作为一个学术科学家和导师的发展。这种优秀的研究环境，通过UAB提供的尖端核心设施将为成功完成本提案和我的培训提供至关重要的支持。research.慢性炎症和免疫反应是梗死后心力衰竭（HF）的组成部分，并决定了随后的梗死愈合和左心室（LV）重塑。几种促炎细胞因子水平增加的鉴定导致针对其中和的治疗努力，其在临床研究中失败。细胞因子水平升高不是潜在病理学的近因，而是激活的炎症反应的结果，这一事实强调了心肌梗死（MI）后炎症和免疫反应在心脏修复中的更复杂作用。在这方面，最近的研究 用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起着至关重要的作用。然而，整体敲除小鼠模型（如CD4-/-）未能考虑时空变化，因为我们看到从急性到慢性HF的进展。尽管如此，可以证明慢性HF期间CD4 + T细胞的作用的临床相关性尚不清楚。 在持续性组织损伤期间，例如在HF中，先天免疫细胞充当抗原呈递细胞以激活效应T细胞和持久记忆T细胞的分化和克隆扩增。因此，在急性期单核细胞和巨噬细胞的强烈活化也意味着T细胞的活化。事实上，我们的初步结果清楚地表明，在慢性HF期间，缺血心肌、循环和重塑脾脏中T细胞的活化和扩增增强。我们的初步结果还表明，T细胞表型的整体时空变化，由TNF α和TNFR 1的表达增强介导，这些经典的促炎信号分子已被证明与HF严重程度和心功能不全临床相关。因此，这意味着T细胞在缺血性心脏中发挥复杂的双相作用，从而使我们假设慢性HF期间促炎表型转换为TNFR1表达在病理上改变了CD4 + T细胞，以促进心脏组织损伤和病理性LV重塑以及HF疾病进展。重要的是，这些是免疫调节的关键细胞靶点。我们将通过i）描绘HF中的总体CD4 + T细胞运输和促炎表型，ii）通过可逆地和特异性地消融转基因CD4-DTR小鼠中的病理性T细胞来建立CD4 + T细胞在LV重塑和慢性HF中的病理生理学作用，和iii）通过TNFR 1+或TNFR 1-CD4 + T细胞的过继转移研究确定TNFR 1 + CD4 + T细胞是否是慢性HF中不利的LV重构所必需和充分的。