The goal in our first of three aims is to integrate data and sample collection from subjects enrolled in the ongoing CTOT-08 trial. On this cohort, additional discovery genomics will be performed, including alternative splicing, mlRNA profiling, epigenetics, multiple single reaction monitoring proteomics of cells and plasma, multiparameter flow cytometry genomics and target gene, pathway-centered genetics. The first objective of this Aim will be to understand what additional discoveries, in terms of biomarkers and mechanisms, are possible by integration of these latest genomic/proteomic technologies. The second objective of this Aim will be to identify patients with specific clinical events and outcomes (e.g. acute rejection and aggressive chronic rejection) that can be studied with freshly purified and activated T and B cell subsets in the context of functional pathways and immunosuppressive therapies identified by the deep sequencing genetics in Project #4, the functional genomics in Project #1, and phosphoproteomlcs in Project #2.
Our second aim will be to discover a new set of biomarker signatures that correlate with the outcomes of patients undergoing kidney transplantation with known levels of anti-donor HLA-specific antibodies following desensitization protocols. Third, we will test the hypothesis that there are common, unifying mechanisms of immunity and inflammation that mechanistically link chronic kidney transplant rejection with the significantly increased risk of catastrophic cardiac events post-transplantation and can be followed by new profiles of blood and/or plasma biomarkers.

Public Health Relevance

The proposed projects have broad relevance for all transplant recipient populations given the burden of chronic immune injury to transplants and the associated systemic effects on the transplant recipients. By advancing the understanding of immune mechanisms involved in transplant rejection while identifying better biomarkers for early diagnosis and intervention, we hope to impact long term survival for these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI063603-10
Application #
8522122
Study Section
Special Emphasis Panel (ZAI1-MFH-I)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$367,164
Indirect Cost
$92,791
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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