T cell Recognition and Injury of Cardiac Allografts

T细胞识别与同种异体心脏移植物的损伤

• 批准号: 7624346
• 负责人: TODD J GRAZIA
• 金额: $ 13.47万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624346
• 关键词: Accounting; Acute; Adrenal Cortex Hormones; Affect; Allografting; Animal Model; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attention; Attenuated; Biological Markers; Biology; Blood Vessels; CD4 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiac; Cells; Cellular Immunity; Cessation of life; Chronic; Clinical; Colorado; Critical Care; Cytotoxic agent; Data; Development; Diagnosis; Doctor of Medicine; Educational Activities; Effector Cell; Endothelial Cells; Environment; Fellowship; Funding; Future; Gene Expression; Genes; Gills; Goals; Graft Rejection; Graft Survival; Grant; Health Sciences; Heart Transplantation; Heart-Lung Transplantation; Human; Immune Targeting; Immune response; Immunology; In Vitro; Inflammation; Inflammatory; Injury; Laboratories; Lead; Lung; Mediating; Medicine; Mentored Clinical Scientist Award; Microarray Analysis; Modeling; Molecular Biology Techniques; Morbidity - disease rate; National Research Service Awards; Nature; Opportunistic Infections; Organ Transplantation; Outcome; Pathway interactions; Patients; Phase; Population; Quality of life; Reactive Oxygen Species; Receptor Signaling; Records; Relative (related person); Reliance; Research; Research Personnel; Risk Factors; Role; Route; Signal Transduction; Signaling Molecule; Solid; T-Cell Activation; T-Lymphocyte; TNF gene; TNFRSF6 gene; Testing; Time; Tissue-Specific Gene Expression; Transplant Recipients; Transplantation; Treatment Protocols; Universities; Vascular Endothelial Cell; Work; Writing; attenuation; career development; cell injury; cell killing; clinical practice; cytokine; cytotoxic; design; heart allograft; improved; in vivo; instructor; interest; mortality; novel; perforin; prevent; protocol development; receptor; research study; response; responsible research conduct; skills

DESCRIPTION (provided by applicant): Candidate: The candidate, Todd Grazia, M.D. is an Instructor in the division of Pulmonary and Critical Care Medicine at the University of Colorado Health Sciences Center. He has currently just completed an NRSA F-32 titled "Antigen Presentation in CD4-mediated Cardiac Rejection." Dr. Grazia has previously worked with vascular endothelial cells and their response to oxygen radicals and inflammation. During his Fellowship, he became interested in clinical heart/lung transplantation. Consequently, he has developed a particular interest in T-cell destructive responses and the role of the allograft endothelial cell as an immune target in cardiothoracic solid organ transplantation. Dr. Grazia's short-term goal is continue to develop both the professional and research skills to become an independent investigator. Long term, Dr. Grazia hopes to develop a successful independently funded laboratory focused on allograft destructive cellular immunity and vascular biology of cardiothoracic solid organ transplantation. This proposed Mentored Clinical Scientist Award would provide him with the support to develop these skills. Career Development: Dr. Grazia's career development will include: 1) development of new research skills, such as the development of well-defined effector cell isolated animal models of cardiac rejection 2) formal educational activities including courses in advanced immunology, molecular biology techniques, responsible research conduct, and grant writing 3) involvement in administrative activities essential to developing professional skills such as serving on the lung Transplant Protocol Development Committee. Environment: Dr. Grazia is currently in an environment that is conducive to excellent research. His sponsor, Dr. Ronald Gill and Collaborator, Dr. Mark Geraci are outstanding extramurally funded independent investigators with established records in research. Research: Current therapy to prevent allograft loss focuses on the inhibition of antigen recognition and costimulatory signaling. However, investigators have not been able to significantly improve graft survival. Consequently, elucidation of T-cell effector mechanisms may allow for a new-targeted approach to abrogate rejection and lengthen significantly the time to chronic rejection. Dr. Grazia's goal will therefore be to elucidate the mechanisms by which effector CD4 and CD8 T-cells kill a cardiac allograft. The hypotheses will be that 1) in vivo CD4 T-cell mediated rejection and in vitro CD4 T-cell mediated endothelial cell injury are dependent on TNF superfamily death receptors, such as TNFR1/2 and/or Fas. 2) in vivo CD8 T-cell mediated rejection is dependent on the cytotoxic molecules, such as perforin and/or Fas. 3) critical genes specific to CD4 versus CD8-mediated rejection can be identified by microarray analysis. Results have the potential to identify critical effector pathways, whose targeted inhibition could lead to attenuation of graft injury and markedly increased patient survival.

描述（由申请人提供）： 候选人：候选人，托德·格拉齐亚（Todd Grazia），医学博士是科罗拉多大学健康科学中心肺部和重症监护医学部的讲师。 他目前刚刚完成了NRSA F-32，名为“ CD4介导的心脏抑制中的抗原表现”。 Grazia博士以前曾与血管内皮细胞及其对氧自由基和炎症的反应。 在奖学金期间，他对临床心脏/肺移植感兴趣。 因此，他对T细胞破坏性反应以及同种异体移植内皮细胞作为心胸固体固体器官移植中的免疫靶标具有特别的兴趣。 Grazia博士的短期目标是继续发展专业和研究技能，成为一名独立研究者。 长期，Grazia博士希望开发成功的独立资助的实验室，专注于同种异体移植破坏性的细胞免疫和心胸部固体器官移植的血管生物学。 这项拟议的指导临床科学家奖将为他提供发展这些技能的支持。 职业发展：Grazia博士的职业发展将包括：1）发展新的研究技能，例如开发明确定义的效应细胞隔离动物模型的心脏拒绝2）正式教育活动，包括高级免疫学课程，分子生物学技术，负责任的研究行为和授予写作3）在诸如诸如lung the Drompts the Lung Transplallant委员会等职业技能的重要性。 环境：格拉齐亚博士目前处于有利于 优秀的研究。 他的赞助商罗纳德·吉尔（Ronald Gill）博士和合作者马克·格拉西（Mark Geraci）博士是杰出的外部资助的独立调查员，拥有研究的既定记录。 研究：预防同种异体损失的当前疗法集中于抑制抗原识别和共刺激信号传导。 但是，研究人员无法显着提高移植物存活率。 因此，阐明T细胞效应器机制可能允许采用新的靶向方法来消除排斥反应并显着延长慢性排斥的时间。 因此，Grazia博士的目标将是阐明效应CD4和CD8 T细胞杀死心脏同种异体移植的机制。 假设是1）体内CD4 T细胞介导的排斥和体外CD4 T细胞介导的内皮细胞损伤取决于TNF超家族死亡受体，例如TNFR1/2和/或FAS。 2）体内CD8 T细胞介导的排斥反应取决于细胞毒性分子，例如穿孔蛋白和/或Fas。 3）可以通过微阵列分析鉴定针对CD4与CD8介导的排斥反应的关键基因。 结果有可能识别关键的效应途径，其靶向抑制可能会导致移植损伤的衰减，并显着增加患者的生存率。