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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：项目摘要候选人。我的长期目标是确保统治轨道教师作为翻译心血管研究的独立研究者的职位。为了实现这一目标，我设计了一项多方面的职业发展计划，具有几个战略短期目标，其中包括i）通过上级研究生级课程进行高级学术培训，ii）通过参加赠款和手稿相关的研讨会，iii）来发展我的写作技巧，iii）与协作研究的网络，iv），iv）参加和现在在国民会议上参加和现在的工作，以及v）出版高影响力的论文。我打算在K99阶段参加这些活动，以便我可以有效地过渡到R0阶段，以独立制定和管理自己的研究计划和研究建议，以提交独立的赠款。我在基础科学方面的培训将着重于获得能力，以在综合心脏生理学（超声心动图和压力量）和T细胞信号机制（TNF-TNFR1 AXIS）的研究中进行先进技术，旨在最终将这些独特的潜水员领域和我的新型恢复范围整合起来，以建立我的独立学术职业。从长远来看，我设想将我的多学科培训纳入药物输送，药理学，毒理学，药代动力学和心血管疾病中，以了解心力衰竭的病理生理学并设计出新颖的翻译策略。凭借我的独特背景和该奖项的支持，我旨在发展学术界和行业之间的有效合作，以成功地将我的研究结果转移到诊所。环境。为了支持我的长期职业目标，我包括了世界著名的临床科学家；医学博士Sumanth D. Prabhu博士和医学博士Louis J. Dell'italia博士积极从事心力衰竭。 T-Cell Biology的专家Casey T Weaver博士和我的心理团队中心脏代谢/昼夜节律节奏专家Martin E. Young博士。研究人员的这种多学科组合为我提供了一个出色而独特的培训环境，以创建成功翻译的心血管调查员。 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）由几位临床科学家和基础研究研究者组成，这些研究人员在潜水学科中具有专业知识，包括生理学，病理学，分子生物学，生物化学和成像。这个多维研究环境将大大支持我作为学术科学家和精神状态的发展。通过UAB提供的这种出色的研究环境，尖端的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。研究。慢性炎症和免疫反应是侵入后心力衰竭（HF）的组成部分，决定了随后的梗塞愈合和左心室（LV）重塑。几种促炎细胞因子的增强水平的鉴定导致了针对其谈判的治疗努力，这在临床研究中失败了。细胞因子水平升高并不是基本病理的直接原因，而是激活炎症反应的结果，强调炎症和免疫反应在心肌梗死（MI）后心脏修复中的更为复杂的作用。在这方面，最近的研究使用CD4 - / - 小鼠表明，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Hind-LIMB肌肉的愈合中起着至关重要的作用。但是，正如我们从急性到慢性HF的进展过程中所看到的那样，全局敲除小鼠模型（例如CD4 - / - ）无法考虑时空变化。但是，尚不清楚可以证明CD4+ T细胞在慢性HF期间的作用的临床相关性。在HF等持续组织损伤期间，先天免疫球充当抗原呈递细胞，以激活效应T细胞的分化和克隆膨胀，并持续的记忆T细胞。因此，急性相的单核细胞和巨噬细胞的强烈激活也意味着T细胞的激活。实际上，我们的初步结果清楚地表明，在慢性HF期间，缺血性心肌，循环和重塑的T细胞的激活和扩展。我们的初步结果还表明，T细胞表型中的全局时空变化是由TNFα和TNFR1的增强表达介导的，TNFα和TNFR1的表达是经典的促炎信号分子，这些信号分子已证明与HF严重程度和心脏功能障碍相关。因此，这意味着T细胞在缺血性心脏中发挥了复杂的双相作用，这使我们假设在慢性HF病理学期间，促炎的表型切换到TNFR1表达会改变CD4+ T细胞，从而改变心脏组织损伤和病理LV重塑和HF疾病进展。重要的是，这些是免疫调节的关键细胞靶标。我们将通过i）通过i）在HF中描述全局CD4+ T细胞运输和促炎表型，ii）确定CD4+ T细胞在LV重塑和慢性HF中的病理生理作用，并通过可逆性地和特定地在Transgenic CD4-DTRS中+ iii+ iii+ TNN定义了TIN+ TTN，并确定ii iii+ ttn。通过TNFR1+或TNFR1- CD4+ T细胞的自适应转移研究，足以在慢性HF中进行不良LV重塑。