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: 8240822
• 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/8240822
• 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. PUBLIC HEALTH RELEVANCE: As of March 2, 2011 2:40 pm Eastern Time, the Organ Procurement and Transplantation Network (http://optn.transplant.hrsa.gov/data/) shows 110,550 candidates who are on a waiting list for organ transplant, of which 87,981 are for kidney transplants. Current treatment strategies are mainly limited to supportive care and new therapeutic interventions to prevent and treat delayed graft function are urgently needed. Exploring dendritic cell-based mechanisms of protection and therapeutic potential in pre-clinical models is essential to determine whether these cells can be used to prevent and treat kidney disease in humans.

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，旨在将我作为树突状细胞免疫机制（DC）S1P1和S1P3依赖的移植抑制的独立研究者。主要的研究重点是延迟移植功能（DGF）到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，这使个人容易受到慢性肾脏疾病，嫁接甚至死亡的丧失。此外，缺血依赖性DGF是移植器官功能的主要决定因素，导致长期有害作用，包括由于增强炎症性免疫反应而导致急性和慢性排斥率提高。肾脏炎症是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端小管鞘氨醇-1-磷酸 - 受体1（S1P1）激活的新作用。肾脏近端小管S1P1激活可保护肾脏免受IRI的侵害。此外，缺乏S13的DC无法在肾脏IRI后诱导先天免疫反应，并且缺乏S13会延长皮肤和心脏移植研究中的移植物存活。此外，VPC01091（S1P1激动剂和S13拮抗剂）治疗可延长皮肤移植的存活，并保护肾脏免受IRI的侵害。我们假设S13的激活和S1P1对DC的抑制作用调节DC成熟，这引发了导致DGF和急性排斥反应的炎症。在当前的提案中，我们将阐明：1）使用遗传方法（使用S1PR3 - / - 和DC特定的S1PR1-/ - 小鼠）DC S1P1和S13激活在啮齿动物肾脏移植模型中的作用，2）S1P受体激发剂，VPC01091的作用，VPC01091的作用 - 使用S1P1和S13的DCS的成熟和激活。从该项目中获得的知识将揭示DC生理学的新方面，并将提供信息，这些信息可以成为未来临床前和临床研究的基础，以探索VPC01091在移植中的治疗潜力。通过该研究计划，我们将1）熟练地熟练于啮齿动物肾移植模型，2）使用体内和维属性免疫学测定法确定与肾脏疾病有关的移植物生存机制，以及3）3）3）对DC的生理学的全面了解，从原始的型肾脏/适应性损伤的背景下，是对DC的生理学的全面理解，受伤期间的模式，DCS中的S1P激动剂和拮抗剂的药理学，其最终目的是建立和资助独立的实验室，重点是治疗慢性肾脏疾病的治疗方法。该研究项目的结果将用于制定由NIH资助的R01申请，该应用程序将在K01奖的后期提交。职业发展计划包括在阿拉巴马大学（UAB）（UAB）的杰出乔治·F·奥布莱恩中心（UAB）的杰出乔治·F·奥布莱恩中心（UAB）的杰出的乔治·奥布莱恩中心（UAB）的教学课程工作，以使我拥有先进和全面的免疫学知识，这将补充现有的肾脏损伤机制的现有知识，从而使我拥有先进和全面的知识。为了获得该奖项，我将获得肾脏伤害机制公认的专家Mark Okusa博士的指导。彼得·洛博（Peter Lobo）（顾问）将提供计划，故障排除和口译结果的其他帮助，以提供移植专业知识，凯文·林奇（Kevin Lynch）博士为药理学化合物的专业知识（VPC01091）提供。成功完成了该培训计划后，我将获得良好的能力，以建立独立的研究职业，以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抑制中的作用。 公共卫生相关性：截至2011年3月2日，下午2:40，器官采购和移植网络（http://optn.transplant.hrsa.gov/data/）显示了110,550名候选人，他们在器官移植的候补名单上，其中87,981个是针对孩子的kidgeneytlplants for Kidney Transpllants的。当前的治疗策略主要限于支持性护理和新的治疗干预措施，以预防和治疗延迟的移植功能。探索基于树突状细胞的保护和治疗潜力的机制对于确定这些细胞是否可用于预防和治疗人类的肾脏疾病至关重要。