Regulatory T Cells as a Novel Therapeutic Agent/Target for Acute Kidney Injury

调节性 T 细胞作为急性肾损伤的新型治疗剂/靶点

• 批准号: 8627231
• 负责人: Gilbert R Kinsey
• 金额: $ 0.08万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627231
• 关键词: Acute Kidney Tubular Necrosis; Acute Renal Failure with Renal Papillary Necrosis; Adenosine; Adenosine A2A Receptor; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Award; Biological Assay; Cell physiology; Cells; Chronic; Clinical; Clinical Research; Colitis; Complement; Dendritic Cells; Dendritic cell activation; Development Plans; End stage renal failure; Family; Foundations; Funding; Future; G-Protein-Coupled Receptors; Genetic; Glycolipids; Goals; Hematopoietic; Hospitalization; Human; Immune; Immune response; Immunologist; Immunology; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Injury; Injury to Kidney; Interferon Type II; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Laboratories; Link; Lymphocyte; Mediating; Mentored Research Scientist Development Award; Mentors; Methods; Morbidity - disease rate; Mus; Natural Immunity; Pathway interactions; Pattern; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Physiology; Positioning Attribute; Pre-Clinical Model; Preparation; Property; Receptor Signaling; Regulatory T-Lymphocyte; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Research Personnel; Research Project Grants; Role; Schools; Supportive care; T-Cell Activation; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Training; Training Programs; Transgenic Mice; United States National Institutes of Health; Work; adaptive immunity; base; career; career development; design; experience; in vivo; killer T cell; loss of function; member; mortality; mouse model; neutrophil; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; protective effect; public health relevance; receptor; receptor expression; renal ischemia; research and development; research study; response; trafficking; treatment strategy

DESCRIPTION (provided by applicant): This Mentored Research Scientist Development Award (K01) application describes a career development and research plan designed to position Dr. Gilbert Kinsey as an independent investigator in immunological mechanisms of, and treatments for, kidney disease. The research focus is acute kidney injury (AKI); a significant clinical problem associated with high morbidity and mortality, which predisposes individuals to chronic and end stage renal disease. Kidney inflammation is well-established as a major pathogenic factor in AKI. Postdoctoral studies by the applicant have recently revealed that regulatory T (Treg) cells, lymphocytes known to suppress adaptive immunity, have the potential to block inflammation, acute tubular necrosis and loss of function in a mouse model of AKI. It is clear from these studies that Treg cells suppress the innate immune response in AKI, which has not been previously demonstrated. Preliminary studies showed that the ability of Treg cells to prevent innate inflammation and renal injury is dependent upon expression of adenosine 2A receptors (A2ARs) on Treg cells. We hypothesize that Treg cells modulate the innate immune response to kidney injury through suppression of a specific innate pathway involving dendritic cells, natural killer T cells and neutrophils, and that pharmacological stimulation of A2A receptors will enhance innate Treg cell functions and represent a new mode of action for A2AR agonists in kidney injury. We will elucidate: 1) the previously uncharacterized mechanism of Treg cell-mediated inhibition of the innate immune response in kidney ischemia-reperfusion injury and 2) a new mechanism of renal protection by A2AR agonists by demonstrating a causal link between Treg cell function and A2ARs. The knowledge gained from this project will reveal new aspects of Treg cell physiology and be a foundation for future pre-clinical and clinical studies to explore the therapeutic potential of regulatory T cells in AKI. Through this research plan the candidate will 1) become proficient with in vitro immunological assays to determine the mechanisms of suppression that are pertinent to kidney disease 2) gain experience with transgenic mouse technology, and 3) develop a comprehensive understanding of the physiology of Treg cells, in the context of kidney injury (from target cells, to mechanisms of suppression, to trafficking patterns during injury, to the pharmacology of an A2AR agonist and antagonist in these cells) with the ultimate goal of establishing and funding an independent laboratory focused on cures and treatments for kidney disease. The results of this research project will be used in the preparation of an independent NIH R01 application that will be submitted in the latter part of the K01 award. The career development plan includes didactic course work to equip Dr. Kinsey with advanced and comprehensive knowledge of immunology, which will complement existing knowledge of mechanisms of kidney injury. For this award, the candidate will be mentored by Dr. Mark Okusa, a recognized expert in immune mechanisms of kidney injury and the anti-inflammatory properties and potential of adenosine A2A receptor agonists in kidney disease. Assistance in planning, troubleshooting, and interpreting results will be provided by Dr. Shyr-Te Ju (consultant), an expert immunologist with extensive in vitro and in vivo expertise with Treg cells. After successful completion of this training program, Dr. Kinsey will emerge well-equipped to establish an independent career in kidney disease research.

描述（由申请人提供）：这一指导的研究科学家发展奖（K01）申请描述了一项职业发展和研究计划，旨在将吉尔伯特·金西（Gilbert Kinsey）博士定位为肾脏疾病的免疫机制和治疗方法的独立研究者。研究重点是急性肾脏损伤（AKI）；与高发病率和死亡率相关的一个重大临床问题，使人倾向于慢性和末期肾脏疾病。肾脏炎症是AKI的主要致病因素。申请人的博士后研究最近表明，已知可抑制适应性免疫的淋巴细胞的调节T（Treg）细胞具有阻断炎症，急性管状坏死和AKI小鼠模型中功能的丧失的潜力。从这些研究中可以明显看出，TREG细胞抑制了AKI中的先天免疫反应，这先前尚未证明。初步研究表明，Treg细胞预防先天炎症和肾损伤的能力取决于Treg细胞上腺苷2A受体（A2AR）的表达。我们假设Treg细胞通过抑制涉及树突状细胞，天然杀伤性T细胞和中性粒细胞的特定先天途径来调节对肾脏损伤的先天免疫反应，并且对A2A受体的药理刺激将增强先天性Treg细胞功能并代表A2AR Agonists在KIDNEY受伤中的新作用模式。我们将阐明：1）先前未表征的Treg细胞介导的机制抑制了肾脏缺血 - 重新灌注损伤的先天免疫反应，以及2）A2AR激动剂的肾脏保护的新机制，通过证明TREG细胞功能之间的因果关系和A2AR之间的因果关系。从该项目中获得的知识将揭示Treg细胞生理的新方面，并为未来的临床前和临床研究探索AKI调节T细胞的治疗潜力的基础。通过该研究计划，候选人将1）熟练地熟练于体外免疫学测定法，以确定与肾脏疾病有关的抑制机制2）获得转基因小鼠技术的经验，以及3）3）3）在肾脏损伤的背景下，对Treg细胞的生理学进行了全面的理解（从靶细胞，与抑制作用的机制，AN抑制作用的机制，AN抑制作用的机制，是ATHNEY损伤的背景细胞）的最终目的是建立和资助独立的实验室，该实验室重点介绍肾脏疾病的治愈和治疗方法。该研究项目的结果将用于准备独立的NIH R01应用程序，该应用将在K01奖的后期提交。职业发展计划包括教学课程工作，以使Kinsey博士对免疫学具有先进和全面的知识，这将补充现有的肾脏损伤机制知识。为此，候选人将由肾脏损伤的免疫机制和抗炎特性和腺苷A2A受体激动剂在肾脏疾病中的公认专家Mark Okusa博士指导。计划，故障排除和解释结果的帮助将由拥有广泛体外和特雷格细胞体内专业知识的专家免疫学家Shyr-Te Ju博士（顾问）提供。成功完成了该培训计划后，Kinsey博士将出现良好的能力，以建立肾脏疾病研究的独立职业。