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.
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.
|Kurian, S M; Velazquez, E; Thompson, R et al. (2017) Orthogonal Comparison of Molecular Signatures of Kidney Transplants With Subclinical and Clinical Acute Rejection: Equivalent Performance Is Agnostic to Both Technology and Platform. Am J Transplant 17:2103-2116|
|Buzby, Jeffrey S; Williams, Shirley A; Schaffer, Lana et al. (2017) Allele-specific wild-type TP53 expression in the unaffected carrier parent of children with Li-Fraumeni syndrome. Cancer Genet 211:9-17|
|Modena, Brian D; Bleecker, Eugene R; Busse, William W et al. (2017) Gene Expression Correlated with Severe Asthma Characteristics Reveals Heterogeneous Mechanisms of Severe Disease. Am J Respir Crit Care Med 195:1449-1463|
|LaMere, Sarah A; Thompson, Ryan C; Meng, Xiangzhi et al. (2017) H3K27 Methylation Dynamics during CD4 T Cell Activation: Regulation of JAK/STAT and IL12RB2 Expression by JMJD3. J Immunol 199:3158-3175|
|Oetting, W S; Schladt, D P; Guan, W et al. (2016) Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles. Am J Transplant 16:574-82|
|Weinsheimer, Shantel; Bendjilali, Nasrine; Nelson, Jeffrey et al. (2016) Genome-wide association study of sporadic brain arteriovenous malformations. J Neurol Neurosurg Psychiatry 87:916-23|
|LaMere, S A; Thompson, R C; Komori, H K et al. (2016) Promoter H3K4 methylation dynamically reinforces activation-induced pathways in human CD4 T cells. Genes Immun 17:283-97|
|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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