Donor organ-specific exosome platform for monitoring transplant organ rejection

用于监测移植器官排斥反应的供体器官特异性外泌体平台

• 批准号: 8683827
• 负责人: Prashanth Vallabhajosyula
• 金额: $ 24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683827
• 关键词: Acute; Animal Model; Area; Biological Assay; Biological Markers; Biology; Biopsy; Blood; Chronic; Clinic; Clinical; Creatinine; Data; Detection; Development; Donor person; Early Intervention; Foundations; Gene Expression Profile; Graft Rejection; HLA Antigens; Health; Heart Transplantation; Heart-Lung Transplantation; Histocompatibility; Human; Immunology; Immunosuppression; Inbred BALB C Mice; Infection; Injury; Kidney; Kidney Transplantation; Link; Liquid substance; Living Donors; Lung; Maintenance; Methods; MicroRNAs; Modeling; Monitor; Morbidity - disease rate; Mus; Organ; Organ Donor; Organ Transplantation; Pathology; Patients; Population; Proteomics; Quality of life; RNA; Reporting; Research; Sampling; Serum; Signal Transduction; Stream; Stress; Techniques; Time; Tissue Donors; Tissues; Titrations; Transplant Recipients; Transplantation; Urine; Visit; Work; arm; base; clinical practice; extracellular; follow-up; improved; in vivo; mortality; mouse model; novel; public health relevance

DESCRIPTION (provided by applicant): Organ transplantation significantly improves patient survival and quality of life. However, majority of patients suffer from complications associated with the transplanted organ, such as acute and chronic rejection, over- immunosuppression, and infection. Currently, there is a critical need for simple, time-sensitive, reliable, and non-invasive methods to monitor transplant patients for donor organ rejection/ injury. Such a biomarker assay would enable early intervention, immunosuppression titration, and thus improve patient morbidity and mortality. This problem is especially relevant to the fields of heart and lung transplantation, where to this date there is no serum biomarker assay to monitor the status of the transplanted heart or lung. Exosomes are extracellular microvesicles released by many tissues into bodily fluids, including blood and urine. They represent stable and tissue-specific proteomic and RNA signature profiles that reflect the conditional state of their tissue of origin. Our group has shown that tissue specific exosome profiles and their RNA signatures are distinct in conditions of health versus injury/ pathology. Therefore, understanding tissue specific exosome profiles from bodily fluids has promise to serve as a "liquid biopsy" of the status of their tissue of origin. No study, to date, has assessed the exosome platform in the context of monitoring transplant organ status, or has shown whether transplant organ releases donor tissue-specific exosomes into the recipient blood/ bodily fluids. To our knowledge, we are the first to report that transplanted organ tissue releases a stable and detectable pool of donor-specific exosomes into the recipient blood/ bodily fluids. Given this proof of novel concept, we hypothesize that donor organ exosome platforms are distinct based on the conditional state of the transplanted organ - maintenance versus rejection/ injury. Therefore, isolation and characterization of transplant organ-specific exosomes and their associated RNA cargo, along with correlation of their differential expression with clinicopathologic data would lay the groundwork for development of a novel, time-sensitive, accurate, and non- invasive biomarker assay to monitor for transplant organ rejection/ injury. Since no study to date has characterized transplant organ specific exosome pools, we propose to investigate this novel concept in two in vivo transplant models: (1) established mouse model of heterotopic heart transplantation under controlled settings of tolerance versus rejection, and; (2) human living donor renal transplantation in the clinical setting. In both settings we will characterize transplant organ specific exosome pools and their RNA signatures in conditions of health versus rejection/ injury to discover distinct profiles associated with organ injury that would serve as the platform for the development of novel biomarker assay to monitor transplant rejection/ injury.

描述（申请人提供）：器官移植可显著提高患者的生存和生活质量。然而，大多数患者会出现与移植器官相关的并发症，如急性和慢性排斥反应、免疫过度抑制和感染。目前，迫切需要一种简单、时间敏感、可靠和无创的方法来监测移植患者的供体器官排斥反应/损伤。这样的生物标志物测定将使早期干预、免疫抑制滴定成为可能，从而改善患者的发病率和死亡率。这个问题与心脏领域特别相关