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 desensitizafion 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI063603-11
Application #
8718975
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Leventhal, J R; Mathew, J M; Salomon, D R et al. (2016) Nonchimeric HLA-Identical Renal Transplant Tolerance: Regulatory Immunophenotypic/Genomic Biomarkers. Am J Transplant 16:221-34
Modena, B D; Kurian, S M; Gaber, L W et al. (2016) Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes. Am J Transplant 16:1982-98
Kurian, Sunil M; Novais, Marta; Whisenant, Thomas et al. (2016) Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures. Theranostics 6:1792-809

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