Genetics of Kidney Transplantation

项目3：肾脏移植的遗传学 在这个项目中，我们建议研究有三种可能结果的肾移植患者(急性排斥、慢性同种异体移植肾病和长期正常功能移植)。我们的目标是确定与这些临床上截然不同的结果相关的遗传因素。我们的第一个论点是，了解与肾移植成败相关的遗传和分子因素将导致个性化的免疫抑制治疗，从而提高移植的成功率，同时降低药物相关的发病率和死亡率。我们的第二个论点是，通过了解决定临床结果的供体器官反应的遗传因素，我们可以确定一种全新的方法来发现新的途径和药物靶点，以提高移植的成功和安全性。对于三种临床上不同的移植表型，我们将确定项目1和2中确定的500个候选基因中的遗传变异，并寻找这些基因中单核苷酸多态(SNP)标记的遗传关联。我们提议的一个独特之处是，供体器官中差异表达的基因也将与供体DNA一起研究。在与Affymetrix的合作中，我们将利用两种强大的基因工具来提高发现速度，同时保持低成本。我们还将利用从国际单倍型图谱项目中获得的知识，并利用SNP基因分型的汇集策略。 该项目的具体目标是： 1.筛选病例间差异基因或蛋白质组表达谱所涉及的候选基因 高密度寡核苷酸综合DNA重测序对遗传关联的控制 微阵列。 2.使用HapMap项目中的单倍型标签SNPs(HtSNPs)筛选候选基因以进行遗传关联 使用混合SNP基因分型方法，然后对相关SNP进行单独SNP基因分型。 3.使用一套高密度SNP微阵列进行全基因组筛查，以进行遗传关联。 4.通过测试预期获得的捐赠者和接受者的第二个队列来验证遗传关联 在该计划项目的头四年期间存档。

Project 3: Genetics of Kidney Transplantation In this project, we propose to study kidney transplant patients with three possible outcomes (acute rejection, chronic allograft nephropathy, and long-term normal functioning transplants). Our objective is to identify the genetic factors associated with these clinically distinct outcomes. Our first thesis is that understanding the genetic and molecular factors associated with the success or failure in renal transplantation will lead to personalized immunosuppressive therapy that increases the success rate of transplantation while decreasing drug-related morbidity and mortality. Our second thesis is that by understanding the genetic elements of donor organ responses to transplantation that determine clinical outcomes, we can identify, a whole new approach to discovering new pathways and drug targets to enhance transplantation success and safety. For each of the three clinically distinct transplant phenotypes, we will identify genetic variations in the 500 gene candidates identified in Projects 1 and 2 and look for genetic association of single nucleotide polymorphism (SNP) markers in these genes. A unique feature of our proposal is that differentially expressed genes in the donor organ will also be pursued with donor DNA. In collaboration with Affymetrix, we will take advantage of two powerful genetic tools to increase the speed of discovery while keeping the cost low. We will also leverage the knowledge gained from the International Haplotype Map Project and take advantage of a pooling strategy for SNP genotyping. The specific aims of this project are: 1. Screen gene candidates implicated by their differential gene or proteome expression profiles between cases and controls for genetic association by comprehensive DNA resequencing with high-density oligonucleotide microarrays. 2. Screen gene candidates using "haplotype-tag SNPs" (htSNPs) from the HapMap Project for genetic association using a pooled SNP genotyping approach followed by individual SNP genotyping of associated SNPs. 3. Conduct whole-genome screening using a set of high-density SNP microarrays for genetic association. 4. Validate the genetic association by testing a second cohort of donors and recipients obtained prospectively and archived during the first four years of the program project.