In this competitive renewal, the 3 over-arching objectives of Project #1 remain the same: a balance of genomic biomarker and biological discovery with direct clinical and translational significance. But In the last 6 years, the field of genomics has changed dramatically and we bring a whole new suite of next generation technologies to bear on these objectives for the new period of funding requested. We have also significantly expanded our scientific team to Include plasma proteomics and heart transplantation (Project #4) and a novel technology platform for multi-parameter flow cytometry genomics (Core B). Finally, we will use our new suite of genomic tools and this carefully crafted and complementary set of scientific Projects to address several new clinical challenges for kidney transplantation that have evolved In this last period: HLA-antibody desensitization and AMR post-transplant, the changing paradigms of chronic rejection, the pressing need to understand how current immunosuppression works and fails, the Increased risks of cardiovascular disease post-transplant and the novel hypothesis that chronic rejection and heart disease are driven by a set of common, unifying mechanisms of immunity/inflammation.
Specific Aim #1 : Use a new generation of genomic technologies to discover biomarker signatures and molecular pathways involved in the development, regulation and outcomes of kidney transplantation Immunity to study the evolution of immunity In 300 kidney transplant patients.
Specific Aim #2 : Apply whole blood, genome-wide gene expression profiling to discover gene expression-based biomarker signatures for acute and chronic antibody-mediated rejection (AMR) in 120 patients with pre-transplant HLA donor antigen-specific antibodies undergoing desensitization and transplantation.
Specific Aim #3 : Advance our mechanistic understanding of chronic kidney transplant rejection by applying the latest genomic profiling technologies detailed In Specific Aim #1.
Specific Aim #4 : Develop new genomic strategies to map the master molecular networks driving T and B cell activation during the development of the post-transplant immune response Including the impact of Immunosuppressive drugs on activation-Induced networks.
The first truth Is that diagnostic practices and management of long term immunosuppresion have not changed significantly in the last decade. The second truth is that graft survival rates at 10-15 years remain unchanged at about 50% and the most common cause of death with a functioning graft remains a catastrophic cardiovascular event. The objective of our work Is to use the latest genomic technologies to address these challenges and in so doing, advance the science and the clinical practice of transplantation.
|Nievergelt, Caroline M; Wineinger, Nathan E; Libiger, Ondrej et al. (2014) Chip-based direct genotyping of coding variants in genome wide association studies: utility, issues and prospects. Gene 540:104-9|
|Scott-Van Zeeland, A A; Bloss, C S; Tewhey, R et al. (2014) Evidence for the role of EPHX2 gene variants in anorexia nervosa. Mol Psychiatry 19:724-32|
|Head, Steven R; Komori, H Kiyomi; LaMere, Sarah A et al. (2014) Library construction for next-generation sequencing: overviews and challenges. Biotechniques 56:61-4, 66, 68, passim|
|Park, Sung Kyu Robin; Aslanian, Aaron; McClatchy, Daniel B et al. (2014) Census 2: isobaric labeling data analysis. Bioinformatics 30:2208-9|
|Norden-Krichmar, Trina M; Gizer, Ian R; Libiger, Ondrej et al. (2014) Correlation analysis of genetic admixture and social identification with body mass index in a Native American community. Am J Hum Biol 26:347-60|
|Magdeldin, Sameh; Yamamoto, Keiko; Yoshida, Yutaka et al. (2014) Deep proteome mapping of mouse kidney based on OFFGel prefractionation reveals remarkable protein post- translational modifications. J Proteome Res 13:1636-46|
|Levitsky, Josh; Mathew, James M; Abecassis, Michael et al. (2013) Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients. Hepatology 57:239-48|
|Bendjilali, Nasrine; Kim, Helen; Weinsheimer, Shantel et al. (2013) A genome-wide investigation of copy number variation in patients with sporadic brain arteriovenous malformation. PLoS One 8:e71434|
|Head, Steven R; Mondala, Tony; Gelbart, Terri et al. (2013) RNA purification and expression analysis using microarrays and RNA deep sequencing. Methods Mol Biol 1034:385-403|
|LaMere, Sarah A; Komori, H Kiyomi; Salomon, Daniel R (2013) New opportunities for organ transplantation research: epigenetics is likely to be an important determinant of the host immune response. Epigenomics 5:243-6|
Showing the most recent 10 out of 47 publications