Biomolecular Markers of Renal Allograft Status

同种异体肾移植状态的生物分子标志物

• 批准号: 8234162
• 负责人: Thangamani Muthukumar
• 金额: $ 13.32万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234162
• 关键词: Acute; Address; Advisory Committees; Advocate; Allogenic; Allografting; Atrophic; Award; Basic Science; Bioinformatics; Biological Assay; Biological Markers; Biological Process; Biology; Biometry; Biopsy; Blood; Blood Cells; Caring; Cell model; Cells; Center for Translational Science Activities; Chronic; Clinical; Clinical Sciences; Commit; Core Facility; Data; Dendritic Cells; Development; Development Plans; Diagnosis; Diagnostic; Diagnostic tests; Enrollment; Environment; Epithelial Cells; Equipment; Faculty; Failure; Fellowship; Fibrosis; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Goals; Graft Rejection; Granzyme; Head; Heart Diseases; Hemorrhage; Human; Immune; Immunogenetics; Immunology; In Vitro; Institutes; Institution; International; Investigation; Kidney; Kidney Failure; Kidney Transplantation; Knowledge; Laboratories; Laboratory Research; Lead; Letters; Literature; Malignant Neoplasms; Master of Science; Medical center; Mentors; Messenger RNA; MicroRNAs; Modeling; Molecular Biology; Molecular Profiling; Multi-Institutional Clinical Trial; Nephrology; New York; Organ Transplantation; Outcome; Patients; Pattern; Performance; Phase; Physicians; Presbyterian Church; Procedures; Protocols documentation; RNA; RNA Sequence Analysis; RNA Sequences; Regulation; Regulator Genes; Regulatory T-Lymphocyte; Research; Research Project Grants; Research Training; Resources; Reverse Transcriptase Polymerase Chain Reaction; Scientist; Serine Protease; Societies; Specimen; Structure; T-Lymphocyte; Technology; Testing; Time; Tissue-Specific Gene Expression; Training; Translating; Translational Research; Transplant Recipients; Transplantation; Tubular formation; United States National Institutes of Health; Universities; Urine; Validation; base; career; career development; cohort; cytotoxic; design; diagnostic accuracy; improved; in vitro Model; insight; interstitial; kidney allograft; knock-down; member; model development; next generation; novel therapeutics; prognostic; programs; public health relevance; skills; urinary

DESCRIPTION (provided by applicant): Candidate: The candidate, a well trained clinician, joined the mentor's laboratory as a research fellow of the International Society of Nephrology. He has identified to date that mRNA for serine proteinase-9, an endogenous antagonist of cytotoxic granzyme, is over expressed in urine during acute rejection (AR) of renal allografts (Muthukumar T et al. Transplantation 2003), and that urinary cell levels of mRNA for Foxp3, a specification for regulatory T cells, are prognostic of AR of renal allografts (Muthukumar T et al. N Engl J Med 2005). He completed his clinical renal fellowship at the New York Presbyterian- Weill Cornell Medical Center (NYPH-WCMC) and joined as a full-time faculty member at NYPH-WCMC from July 1, 2009. He has initiated studies on intragraft micro RNA expression patterns upon re-joining the mentor's laboratory. Environment: Our institution, NYPH-WCMC advocates free scientific exploration within our tri-institutional network that is comprised of Weill Cornell, Memorial Sloan Kettering Cancer Institute and the Rockefeller University. Some of the significant features of the environment are: (1) the mentor's PCR core research laboratory with an excellent track record in the development/refinement of quantitative PCR assays and participation as the PCR Core in NIH sponsored multi-center clinical trials of organ transplantation utilizing state-of-the art equipment for mRNA/miRNA profiling; (ii) the interdisciplinary renal transplant program at our institution; (iii) the candidate's excellent co-mentors comprised of Drs. F. Campagne (Bioinformatics, Weill Cornell), R. Ding (Molecular Biology, Weill Cornell), J.E. Schwartz (Biostatistics, Weill Cornell/Columbia), R.M. Steinman (Immunology, Rockefeller) and T. Tuschl (RNA Biology, Rockefeller); (iv) Core facility laboratories with state-of-the art technologies; (v) an Institute of Computational Biomedicine providing outstanding bioinformatics support, (vi) the Clinical Immunogenetics Laboratory directed by the mentor; and (vii) the NIH sponsored Clinical and Translational Science Center at Weill Cornell. Research: Candidate's Immediate Goal: To further develop research skills, and become an independent physician-scientist through structured and progressively independent training with research and didactic components. Candidate's Long-Term Goal: To improve knowledge in the transplantation field and help translate basic research findings to the bedside and optimize organ transplantation. Research Career Development Plan: Our plan incorporates both research training via performance of translational research and didactic activities. During the award period, the candidate will commit a minimum of 75% effort towards career development and training towards becoming an independent physician scientist. The research proposed is also designed to use a biologic approach to address the basis for differential gene expression patterns as well development of novel therapeutics in the future. In addition, the candidate's co- mentors are outstanding scientists with expertise highly relevant to the candidate's new training and career progression, and will provide training, formally review his progress and facilitate, along with his mentor, his transition to an independent physician-scientist. The candidate and his mentor will interact both formally and informally in a number of settings on a weekly basis. The candidate will have access to and will take full advantage of the resources available in our neighboring tri-institutional network, to further enhance his skills and to acquire knowledge. He has enrolled in the K30 Master of Science in Clinical & Translational Investigation, offered by the Clinical & Translational Science Center at Weill-Cornell. Research Project: Renal transplantation is the preferred treatment for irreversible kidney failure. Short term outcomes have improved over the years, nevertheless, almost 50% fail by 10 years. Acute rejection (AR) and interstitial fibrosis/tubular atrophy (IF/TA) are significant contributors to allograft failure. AR and IF/TA are currently diagnosed using the invasive biopsy procedure. Development of noninvasive biomarkers of renal allograft status is an important goal. The candidate will take advantage of next-generation sequencing, a revolutionary technology to discover intragraft biomarkers of AR and IFTA. He will then use RT-PCR assays, improved in the Mentor's laboratory to yield absolute copy numbers of mRNAs/miRNAs, in the validation phase of the study. He will profile urinary cells and peripheral blood cells to develop noninvasive biomolecular markers predictive of renal allograft status. To better understand mechanisms and facilitate future development of specific therapies, he will establish in-vitro cellular models mimicking AR and IF/TA and characterize mRNA/miRNA profiles and investigate the regulation of mRNAs by short inhibitory RNAs. SA.1: To discover and validate biomarkers of AR and IF/TA by characterizing the transcriptome of renal allograft biopsies classified as AR, IF/TA or normal. SA.2: To establish in-vitro cellular models and characterize transcriptomes under conditions mimicking AR or IF/TA and investigate whether mRNAs associated with AR and IF/TA can be regulated with siRNAs. SA.3: To develop noninvasive biomarkers of AR and IF/TA by mRNA/miRNA profiling of urinary cells and peripheral blood cells. Study specimens (allograft biopsies, urine and blood) will be from kidney transplant recipients enrolled in two-NIH-sponsored studies; R37 AI051652 and U01 AI08446.

描述（由申请人提供）：候选人：候选人，训练有素的临床医生，加入了导师的实验室，成为国际肾脏病学会的研究员。 He has identified to date that mRNA for serine proteinase-9, an endogenous antagonist of cytotoxic granzyme, is over expressed in urine during acute rejection (AR) of renal allografts (Muthukumar T et al. Transplantation 2003), and that urinary cell levels of mRNA for Foxp3, a specification for regulatory T cells, are prognostic of AR of renal allografts （Muthukumar T等人N Engl J Med 2005）。他在纽约长老会 - 威尔·康奈尔医学中心（NYPH-WCMC）完成了临床肾脏研究金，并从2009年7月1日开始在Nyph-WCMC担任全职教职员工。他在重新加入导师的实验室时就开始了对手册内微RNA表达模式的研究。环境：我们的机构NYPH-WCMC主张我们的三机构网络中的自由科学探索，该探索由Weill Cornell，纪念Sloan Kettering Cancer Institute和Rockefeller University组成。环境的某些重要特征是：（1）导师的PCR核心研究实验室，在定量PCR分析的开发/完善中具有出色的记录，并作为NIH赞助的PCR核心作为NIH赞助的多中心临床试验的PCR核心，利用MRNA/miRNA的ART ART NABLICENT ORNATER TRAPTLATITION的器官移植； （ii）我们机构的跨学科肾移植计划； （iii）由DRS组成的候选人的出色副委托人。 F. Campagne（生物信息学，Weill Cornell），R。Ding（Molecular Biology，Weill Cornell），J.E。Schwartz（生物统计学，Weill Cornell/Columbia），R.M。 Steinman（免疫学，洛克菲勒）和T. tuschl（RNA Biology，Rockefeller）； （iv）具有最先进技术的核心设施实验室； （v）一个计算生物医学研究所提供了出色的生物信息学支持，（vi）导师指导的临床免疫遗传学实验室； （vii）NIH赞助了Weill Cornell的临床和转化科学中心。研究：候选人的直接目标：通过结构化和逐步独立的研究和教学成分来进一步发展研究技能，并成为独立的医师科学家。候选人的长期目标：提高移植场的知识并有助于将基础研究发现转化为床边并优化器官移植。研究职业发展计划：我们的计划通过转化研究和教学活动进行了研究培训。在奖励期间，候选人将至少付出75％的努力，为职业发展和培训成为一名独立的医师科学家。提出的研究还旨在使用一种生物学方法来解决差异基因表达模式的基础，以及未来新型治疗剂的发展。此外，候选人的合伙人是杰出的科学家，具有与候选人的新培训和职业发展高度相关的专业知识，并将提供培训，正式审查他的进步，并促进他的导师，并与他的导师过渡到独立的医师科学家。候选人及其导师将每周在许多环境中正式和非正式地进行互动。候选人将可以访问并将充分利用我们邻近的三机构网络中可用的资源，以进一步提高他的技能并获取知识。他曾在Weill-Cornell的临床与转化科学中心提供临床和翻译研究的K30科学硕士学位。研究项目：肾移植是不可逆肾衰竭的首选治疗方法。多年来，短期结果有所提高，然而，将近50％的失败了10年。急性排斥（AR）和间质纤维化/管状萎缩（如果/TA）是同种异体移植失败的重要促进者。 AR和IF/TA当前使用侵入性活检程序进行诊断。发展肾脏同种异体状态的无创生物标志物是一个重要目标。候选人将利用下一代测序，这是一种革命性的技术，可以发现AR和IFTA的内部生物标志物。然后，他将在研究验证阶段使用RT-PCR分析，并在导师的实验室中改进了MRNA/miRNA的绝对拷贝数。他将介绍泌尿细胞和外周血细胞，以形成可预测肾脏同种异体状态的非侵入性生物分子标记。为了更好地理解机制并促进了特定疗法的未来开发，他将建立模仿AR的体外细胞模型，以及IF/ta并表征mRNA/miRNA谱并通过短抑制性RNA调节mRNA。 SA.1：通过表征分类为AR的肾脏同种异体活检的转录组，发现和验证AR的生物标志物和IF/TA。 SA.2：在模仿AR的条件下或IF/ta的条件下建立体外细胞模型并表征转录组，并研究是否与AR相关的mRNA和IF/ta可以通过siRNA进行调节。 SA.3：通过尿细胞和外周血细胞的mRNA/miRNA分析，开发AR和IF/TA的非侵入性生物标志物。研究标本（同种异体移植活检，尿液和血液）将来自参与两项NIH赞助研究的肾脏移植受者。 R37 AI051652和U01 AI08446。