Cytomegalovirus and Chronic Renal Allograft Rejection

巨细胞病毒和慢性同种异体肾移植排斥

基本信息

批准号：
7206639
负责人：
Masako Shimamura
金额：
$ 9.32万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-05 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7206639
关键词：
Alabama Allografting Animal Model Basement membrane Biopsy Cell Adhesion Cell Line Cells Childhood Chronic Clinical Communicable Diseases Cytomegalovirus Cytomegalovirus Infections Data Development Diagnosis Diagnostic Dialysis procedure Disease Disruption Endopeptidases Epithelial Cells Epithelium Extracellular Matrix Extracellular Matrix Degradation Extracellular Matrix Proteins Feedback Fibrosis Foundations Functional disorder Future Genes Genetic Transcription Goals Histologic Human Immunohistochemistry Immunologist In Situ Hybridization In Vitro Infection Kidney Kidney Diseases Kidney Transplantation Link Mediating Metalloproteases Modeling Molecular Molecular Biology Molecular Virology Morbidity - disease rate Mus Organ Transplantation Outcome Pathogenesis Pathway interactions Patients Peptide Hydrolases Phenotype Physical Dialysis Production Protein Biosynthesis Public Health Rat Cytomegalovirus Rattus Renal Tissue Research Research Personnel Scientist Solid Specialist Staging Testing Therapeutic Tissues Training Transforming Growth Factors Translational Research Transplant Recipients Transplantation Tubular formation Universities Virus Diseases Work Yang base career cost cytokine epithelial to mesenchymal transition extracellular graft function improved in vivo inhibitor/antagonist insight interstitial kidney allograft novel novel diagnostics prevent programs

项目摘要

DESCRIPTION (provided by applicant): Dr. Shimamura is a pediatric infectious diseases specialist whose career goal is to establish a molecular and translational program in solid organ transplant infectious diseases, focusing upon viral infections in transplant recipients. She plans to pursue clinician-scientist training under the tutelage of Dr. William J. Britt, noted herpesvirologist, and Dr. Mark Benfield, transplant immunologist and national leader in pediatric renal transplant research. Formal molecular biology coursework and clinical transplant infectious diseases training outlined in this proposal will provide her with the educational foundation for future research in molecular virology, transplant infections, and patient-based translational research to determine causes and treatments for infections related to solid organ transplantation. Dr. Shimamura is based at the University of Alabama-Birmingham, which has a nationally recognized solid organ transplantation program. Dr. Shimamura studies human cytomegalovirus (HCMV), which has been linked epidemiologically to chronic renal allograft rejection and long-term graft loss, but the pathogenesis remains poorly understood. She has identified a novel mechanism by which HCMV may promote renal fibrosis via activation of transforming growth factor-¿1 (TGF-¿1), a potent pro-fibrotic cytokine found in renal allografts during chronic rejection. TGF-¿1 triggered matrix metalloprotease (MMP) production is also enhanced by HCMV infection of renal tubular cells. These data implicate a positive feedback loop between TGF-¿1, MMPs, and HCMV promoting fibrosis contributing to renal allograft dysfunction. This study will: (1) characterize the MMP-driven mechanism by which HCMV-infected cells activate TGF-¿1; (2) determine the HCMV gene(s) promoting TGF-¿1 activation; and (3) establish an in vivo murine model for CMV enhanced chronic renal allograft fibrosis. The long-term goal is to develop diagnostic and therapeutic strategies to prevent or abrogate CMV related renal fibrosis during chronic renal allograft rejection, thus preserving graft function in HCMV infected patients with chronic renal allograft rejection. Public Health Relevance: This research will provide insight into the molecular pathogenesis of cytomegalovirus contributions to renal fibrosis during chronic renal allograft rejection. Such studies will assist in development of new diagnostic strategies and treatments against chronic rejection to prevent long-term allograft loss in kidney transplant recipients, avoiding the cost and morbidity of long-term dialysis or re-transplantation in these patients.

描述（由申请人提供）：Shimamura 博士是一名儿科传染病专家，其职业目标是建立实体器官移植传染病的分子和转化项目，重点关注移植受者的病毒感染，她计划接受临床医生科学家培训。在著名疱疹病毒学家 William J. Britt 博士和移植免疫学家、儿科肾移植研究国家领导者 Mark Benfield 博士的指导下，本文概述了正式的分子生物学课程和临床移植传染病培训。该提案将为她未来在分子病毒学、移植感染和基于患者的转化研究方面的研究提供教育基础，以确定与实体器官移植相关的感染的原因和治疗方法。 Shimamura 博士在阿拉巴马大学伯明翰分校工作，该大学拥有全国认可的实体器官移植项目，研究人类巨细胞病毒 (HCMV)，该病毒在流行病学上与慢性同种异体肾移植排斥和长期移植物丢失有关。但其发病机制仍知之甚少，她发现了 HCMV 通过激活转化生长因子促进肾纤维化的新机制。 1 (TGF-¿1)，一种在慢性排斥反应期间同种异体肾移植物中发现的有效促纤维化细胞因子。肾小管细胞的 HCMV 感染也会增强 TGF-β1 触发的基质金属蛋白酶 (MMP) 的产生，这些数据表明 TGF-¿ 1、MMP 和 HCMV 促进纤维化，导致同种异体移植肾功能障碍。这项研究将：(1) 表征 HCMV 感染细胞激活 TGF-¿ 的 MMP 驱动机制1；(2)确定促进TGF-¿的HCMV基因1 激活；(3) 建立 CMV 增强的慢性同种异体移植肾纤维化的体内小鼠模型。长期目标是开发诊断和治疗策略，以预防或消除慢性同种异体移植肾排斥期间 CMV 相关的肾纤维化，从而保护移植物。 HCMV 感染患者慢性肾同种异体移植排斥反应的功能。公共健康相关性：这项研究将深入了解巨细胞病毒在慢性肾同种异体移植排斥过程中导致肾纤维化的分子发病机制，此类研究将有助于开发针对慢性排斥的新诊断策略和治疗方法，以防止肾移植中的长期同种异体移植物丢失。接受者，避免这些患者长期透析或再次移植的费用和发病率。