The genetics of transplantation is unique and fascinating. When a donor organ is placed in the recipient's body, two genomes (each with unique properties) interact under the influence of immunosuppressive agents to produce life-saving results. However, In some cases, the recipient's immune system rejects the foreign organ, leading to the destruction of the donor organ. The success or failure of kidney transplantation is undoubtedly Influenced by genetics. In this project, we propose to pursue the pathways previously discovered to influence kidney transplantation outcome utilizing the newest DNA target capture/sequencing technologies to identify the genetic variations that correlate with acute rejection and chronic rejection (CAN/IFTA with inflammation) in kidney transplants. Taking advantage of the large kidney transplant cohort assembled by our collaborators, we will perform deep DNA sequencing of all human exons and the high value non-coding regions of ~2000 genes in pathways associated with kidney transplantation outcome in 600 donor and recipient DNA samples from subjects with "extreme phenotypes". For example, we will sequence subjects who develop acute rejection or chronic rejection much faster than the average kidney transplant patient. In addition, we will study patients that are >5 years post-transplant and have normal and stable kidney transplant function (sCr <1.5 mg/dl). Variants identified will be validated by Sanger sequencing and their genetic effects studied by typing the variants against a large cohort of kidney transplant patients. The variants that are highly correlated with kidney transplantation outcome and most likely to affect gene expression or gene function will be selected for biological validation In functional studies using freshly purified blood cells from independently collected kidney transplants with the correlative clinical phenotypes.
Recent advances in DNA sequencing technology and the identification of pathways associated with kidney transplantation outcomes provide us with an opportunity to search for the genetic variants that cause acute and chronic rejection in a comprehensive way. If successful, our project will Identify genetic factors that give us insights into the biological basis for graft rejection in kidney transplantation and provide new biomarkers for diagnosis and targets for drug development.
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