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: 8432025
• 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/8432025
• 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; Genetic; 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; 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）申请描述了我的职业发展和研究计划，旨在将我定位为树突状细胞（DC） S1P1和S1P3依赖性移植排斥的免疫学机制的独立研究者。主要的研究重点是移植中的延迟移植功能（DGF）进展到急性排斥反应，这是一个重要的临床问题，与高发病率和死亡率相关，它使个体易患慢性肾脏疾病和移植物丢失甚至死亡。此外，缺血依赖性DGF是移植器官功能的主要决定因素，导致长期有害影响，包括炎症免疫反应增强导致的急性和慢性排斥反应率增加。肾脏炎症是急性排斥反应的主要致病因素。作为博士后，我最近的工作揭示了肾近端小管鞘氨醇-1-磷酸受体-1 （S1P1）激活的新作用。肾近端小管S1P1激活可保护肾脏免受IRI。此外，在皮肤和心脏移植研究中，缺乏S1P3的dc不能诱导肾脏IRI后的先天免疫反应，并且缺乏S1P3延长了移植物的存活时间。此外，VPC01091 （S1P1激动剂和S1P3拮抗剂）治疗延长皮肤移植存活并保护肾脏免受IRI。我们假设S1P3的激活和DC上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。在目前的建议中，我们将阐明：1)通过遗传学方法（使用S1pr3-/-和DC特异性S1pr1-/-小鼠）阐明DC S1P1和S1P3激活在啮齿动物肾移植模型中的作用，2)S1P受体激动剂VPC01091在肾移植中的作用，以及3)使用缺乏S1P1和S1P3的DC成熟和激活的体外机制。从本项目中获得的知识将揭示DC生理学的新方面，并将为未来的临床前和临床研究提供信息，以探索VPC01091在移植中的治疗潜力。通过这一研究计划，我们将1)熟练掌握啮齿动物肾移植模型，2)利用体内和体外免疫分析来确定与肾脏疾病相关的移植物存活机制，3)在肾损伤背景下对DC的生理学（从先天/适应性免疫的靶细胞，到DC成熟的机制，再到损伤期间的转运模式）有一个全面的了解。到一种S1P激动剂和拮抗剂在dc中的药理学)，最终目标是建立和资助一个独立的实验室，专注于慢性肾脏疾病的治疗。该研究项目的结果将用于准备独立的NIH资助的R01申请，该申请将在K01奖的后半部分提交。我的职业发展计划包括在阿拉巴马大学（UAB）优秀的George F. O'Brien中心（Core B）的Anupam Agarwal博士的指导下进行肾移植方面的全面培训，教学课程使我具备先进而全面的免疫学知识，这将补充现有的肾损伤机制知识。对于这个奖项，我将由Mark Okusa博士指导，他是公认的肾损伤免疫机制专家。移植专家Peter Lobo博士（顾问）和药理学化合物专家Kevin Lynch博士（VPC01091）将提供计划、故障排除和结果解释方面的额外协助。在顺利完成该培训项目后，我将有能力建立独立的研究生涯，探索鞘脂受体在移植中的作用，重点研究适应性免疫反应和鞘脂受体和激酶在慢性排斥反应中的作用。