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.
Kidney transplantation is the best treatment for patients with permanent kidney failure. Immune rejection and chronic kidney damage however occur frequently and result in kidney transplant failure. Until now, diagnosis of transplant rejection required a biopsy which may cause bleeding and damage to the kidney. I propose to develop gene based diagnostic tests using blood and urine, and obviate the need for transplant biopsies. I also plan to study the biologic mechanisms involved in immune rejection and kidney damage. My new training in state of the art technologies (e.g., RNA sequencing) and the proposed research should serve as an effective vehicle for my development into an independent physician scientist as well as improve the care of future patients.
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