Defining the functional impact of T1D genes in mouse and man: a unified strategy

描述（由申请人提供）：很明显，基因在T1 D的发展中起着重要作用。已经取得了进展，但一些障碍阻碍了在确定与T1 D风险相关的基因的功能后果方面的进展。这些包括与单个基因组区域相关的适度风险和关于这些区域中哪些SNP是致病性的不确定性，限制了将基因型与表型相关的机制研究。基因的多样性和个体间的异质性给人类受试者中基因变异的功能后果的研究带来了进一步的复杂性，而小鼠模型可能无法反映基因对人类免疫应答的影响。为了克服这些障碍中的每一个，我们提出了一种新的策略，通过整合三种不同的方法来定义T1 D中新的遗传变异的功能意义：目的1：我们将利用新的遗传方法来鉴定T1 D中的致病遗传基因座，从而鉴定可以在小鼠和人中以靶向方式研究的变异。我们将在小鼠中模拟致病变异，使我们能够研究遗传变异对免疫发育的影响，在多个细胞群中以及对体内抗原暴露的反应。目的3：我们将定义与T1 D患者和非T1 D患者中这些致病性遗传变异相关的功能表型。这些研究将部分由鼠模型中的发现驱动，同时还将确定这些模型的发现与人类受试者和T1 D的相关性。每个目标将由各自领域的专家指导，该专家在T1 D的基因型-表型研究中具有成功合作的良好记录。这种方法的独特之处在于，尽管每个目标的方法都是不同的，但本项目每个目标的结果都会影响其他目标的方向和实验设计。目标2和目标3中的初步研究将侧重于通过遗传研究工作已经确定的编码变体; PTPN 22、SH 2B 3、TYK 2和IFIH 1。未来使用该综合策略的研究将纳入目标1-定义与T1 D相关的额外致病性遗传变异中进行的B研究所识别的遗传变异。这些方法的整合将克服目前限制T1 D遗传学进展的障碍，将增强我们对几种T1 D相关遗传变异的理解，还将开发一个研究其他基因的平台，以促进对T1 D疾病发病机制的更好理解。

DESCRIPTION (provided by applicant): It is clear that genes play a significant role in the development of T1D. Progress has been made but several hurdles have impeded progress in defining the functional consequences of the genes associated with T1D risk. These include the modest risk associated with individual genomic regions and uncertainty as to which of the SNPs in these regions are causative limiting mechanistic studies relating genotype to phenotype. The multiplicity of genes and the heterogeneity among individuals poses further complexity to the study of the functional consequences of variation in genes in the human subjects, while murine models may not reflect the impact of a gene on the human immune response. To overcome each of these hurdles we propose a novel strategy to define the functional significance of novel genetic variants in T1D by integrating three different approaches: Aim 1: We will utilize a novel genetic approach to identify causative genetic loci in T1D thus identifying variants that can be studied in a targeted manner in mouse and man. Aim 2: We will model causative variants in mice allowing us to study the impact of the genetic variants on immune development, in multiple cell population and in response to in vivo antigen exposure. Aim 3: We will define the functional phenotypes related to these causative genetic variants in humans with and without T1D. The studies will be in part driven by findings in murine models while they will also determine the relevance of findings from these models to human subjects and T1D. Each aim will be directed by an expert in their field, who has a strong track record for successful collaboration in genotype- phenotype studies of T1D. This approach is unique in that although each Aim will be distinct in its approach findings from each Aim of this project will influence the direction and experimental design of the other aims. The initial studies in Aim 2 and 3 will focus on coding variants already identified through the work of genetic studies; PTPN22, SH2B3, TYK2 and IFIH1. Future studies using this integrated strategy will incorporate genetic variants identified b studies performed in Aim 1- defining addition causative genetic variants associated with T1D. The integration of these approaches will overcome hurdles that now limit progress in T1D genetics, will enhance our understanding of several T1D associated genetic variants, and will also develop a platform for studies of additional genes that will promote a better mechanistic understanding of T1D disease pathogenesis.