Sphingosine 1 phosphate receptors 1 and 3 as novel targets in transplantation

鞘氨醇 1 磷酸受体 1 和 3 作为移植新靶点

• 批准号: 9000694
• 负责人: Amandeep Bajwa
• 金额: $ 11.59万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000694
• 关键词: Acute; Adverse effects; Agonist; Alabama; Alloantigen; Allografting; Antigens; Area; Attenuated; Award; Biological Assay; Cell Maturation; Cell physiology; Cells; Cessation of life; Chronic; Chronic Kidney Failure; Clinical; Clinical Research; Complement; Cytokine Activation; Data; Dendritic Cells; Development Plans; Foundations; Funding; Future; G-Protein-Coupled Receptors; Goals; Graft Rejection; Graft Survival; Heart; Heart Transplantation; Human; Immune; Immune response; Immunobiology; Immunology; Immunosuppressive Agents; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Injury; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Laboratories; Leukocytes; Ligands; Link; Mentored Research Scientist Development Award; Mentors; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Nephrology; Organ; Organ Procurements; Organ Survival; Organ Transplantation; Outcome; Pathogenesis; Pathway interactions; Pattern; Performance; Pharmacology; Phenotype; Phosphotransferases; Physiology; Play; Positioning Attribute; Postdoctoral Fellow; Pre-Clinical Model; Preparation; Production; Property; Proximal Kidney Tubules; Regimen; Reperfusion Injury; Research; Research Personnel; Research Project Grants; Rodent; Role; Signal Transduction; Skin; Skin Transplantation; Skin graft; Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptor; Supportive care; T-Lymphocyte; Therapeutic; Time; Training; Training Programs; Transplantation; United States National Institutes of Health; Universities; Waiting Lists; Work; adaptive immunity; allograft rejection; base; career; career development; cell injury; cell motility; chemokine; cytokine; delayed graft function; design; effective therapy; end-stage organ failure; genetic approach; graft function; in vivo; isoimmunity; mortality; new technology; novel; novel therapeutic intervention; pre-clinical; preclinical study; prevent; programs; receptor; renal ischemia; research and development; response; skills; sphingosine 1-phosphate; therapeutic target; 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 me as an independent investigator in immunological mechanisms of dendritic cell (DC) S1P1 and S1P3 dependent transplant rejection. The main research focus is progression of delayed graft function (DGF) to acute rejection in transplantation, a significant clinical problem associated with high morbidity and mortality, which predisposes individuals to chronic renal disease and loss of graft or even death. Furthermore, ischemia dependent DGF is a major determinant of organ function in transplantation, leading to long-term deleterious effects, including increased rate of acute and chronic rejection as a consequence of enhancement of inflammatory immune response. Kidney inflammation is well-established as a major pathogenic factor in acute rejection. My work as a postdoctoral fellow has recently revealed a novel role of kidney proximal tubule sphingosine-1-phosphate-receptor-1 (S1P1) activation. Kidney proximal tubule S1P1 activation protects kidneys from IRI. In addition, DCs lacking the S1P3 are unable to induce an innate immune response after kidney IRI and lack of S1P3 prolongs graft survival in skin and heart transplantation studies. Additionally, VPC01091 (S1P1 agonist and S1P3 antagonist) treatment prolongs skin graft survival and protects kidneys from IRI. We hypothesize the activation of S1P3 and inhibition of S1P1 on DC regulates DC maturation, which initiates inflammation leading to DGF and acute rejection. In the current proposal, we will elucidate: 1) the role of DC S1P1 and S1P3 activation in rodent kidney transplantation model by using genetic approaches (use of S1pr3-/- and DC specific S1pr1-/- mice), 2) the role of S1P receptor agonist, VPC01091, pharmacological approach in kidney transplantation, and 3) in-vitro mechanisms of DC maturation and activation using DCs deficient of S1P1 and S1P3. The knowledge gained from this project will reveal new aspects of DC physiology and will provide information that can be a foundation for future pre-clinical and clinical studies to explore the therapeutic potential of VPC01091 in transplantation. Through this research plan we will 1) become proficient with rodent kidney transplant model, 2) utilize in-vivo and in-vitro immunological assays to determine the mechanisms of graft survival that are pertinent to kidney disease, and 3) develop a comprehensive understanding of the physiology of DCs, in the context of kidney injury (from target cells of innate/adaptive immunity, to mechanisms of DC maturation, to trafficking patterns during injury, to the pharmacology of an S1P agonist and antagonist in DCs) with the ultimate goal of establishing and funding an independent laboratory focused on cures and treatments for chronic kidney diseases. The results of this research project will be used in the preparation of an independent NIH funded R01 application that will be submitted in the latter part of the K01 award. The career development plan includes thorough training in kidney transplantation under the guidance of Dr. Anupam Agarwal at the outstanding George F. O'Brien Center (Core B) at the University of Alabama (UAB), didactic course work to equip me with advanced and comprehensive knowledge of immunology, which will complement existing knowledge of mechanisms of kidney injury. For this award, I will be mentored by Dr. Mark Okusa, a recognized expert in immune mechanisms of kidney injury. Additional assistance in planning, troubleshooting, and interpreting results will be provided by Dr. Peter Lobo (consultant) for expertise in transplantation and Dr. Kevin Lynch for expertise in pharmacological compounds (VPC01091). After successful completion of this training program, I will emerge well-equipped to establish an independent research career in exploring the role of sphingosine receptors in transplantation with focus on adaptive immune response and role of sphingolipid receptors and kinases in chronic rejection.

描述（由申请人提供）：这份指导研究科学家发展奖 (K01) 申请描述了一项职业发展和研究计划，旨在使我成为树突状细胞 (DC) S1P1 和 S1P3 依赖性移植排斥的免疫学机制的独立研究者。主要研究重点是移植物功能延迟（DGF）进展为移植中的急性排斥反应，这是一个与高发病率和死亡率相关的重大临床问题，使个体容易患上慢性肾病和移植物丢失甚至死亡。此外，缺血依赖性DGF是移植中器官功能的主要决定因素，导致长期有害影响，包括由于炎症免疫反应增强而导致急性和慢性排斥反应发生率增加。肾脏炎症已被确定为急性排斥反应的主要致病因素。我作为博士后研究员的工作最近揭示了肾近曲小管 1-磷酸鞘氨醇-1 (S1P1) 激活的新作用。肾近曲小管 S1P1 激活可保护肾脏免受 IRI 侵害。此外，缺乏 S1P3 的 DC 无法在肾脏 IRI 后诱导先天免疫反应，并且在皮肤和心脏移植研究中，缺乏 S1P3 可以延长移植物的存活时间。此外，VPC01091（S1P1 激动剂和 S1P3 拮抗剂）治疗可延长植皮存活率并保护肾脏免受 IRI 影响。我们假设 DC 上 S1P3 的激活和 S1P1 的抑制调节 DC 成熟，从而引发炎症，导致 DGF 和急性排斥反应。在当前的提案中，我们将阐明：1）通过使用遗传方法（使用 S1pr3-/- 和 DC 特异性 S1pr1-/- 小鼠）在啮齿动物肾移植模型中激活 DC S1P1 和 S1P3 的作用，2） S1P 受体激动剂、VPC01091、肾移植的药理学方法，以及 3) 使用缺乏 S1P1 的 DC 进行 DC 成熟和激活的体外机制和S1P3。从该项目中获得的知识将揭示 DC 生理学的新方面，并将提供可以为未来临床前和临床研究奠定基础的信息，以探索 VPC01091 在移植中的治疗潜力。通过这项研究计划，我们将 1) 精通啮齿动物肾移植模型，2) 利用体内和体外免疫学测定来确定与肾脏疾病相关的移植物存活机制，以及 3) 全面了解肾损伤背景下 DC 的生理学（从先天/适应性免疫的靶细胞，到 DC 成熟机制，到损伤期间的运输模式，到 S1P 激动剂和拮抗剂的药理学） DC）的最终目标是建立并资助一个专注于慢性肾脏疾病治愈和治疗的独立实验室。该研究项目的结果将用于准备 NIH 资助的独立 R01 申请，该申请将在 K01 奖项的后期提交。职业发展计划包括在阿拉巴马大学 (UAB) 杰出的乔治 F. 奥布莱恩中心（核心 B）的 Anupam Agarwal 博士的指导下进行全面的肾移植培训，以及为我提供先进和实用知识的教学课程。免疫学的全面知识，将补充现有的肾损伤机制知识。对于这个奖项，我将得到肾损伤免疫机制领域公认的专家 Mark Okusa 博士的指导。移植方面的专业知识 Peter Lobo 博士（顾问）和药理化合物方面的专业知识 Kevin Lynch 博士 (VPC01091) 将提供计划、故障排除和解释结果方面的额外帮助。成功完成本培训计划后，我将有能力建立独立的研究生涯，探索鞘氨醇受体在移植中的作用，重点关注适应性免疫反应以及鞘脂受体和激酶在慢性排斥中的作用。