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T1D的发展中起着重要的作用。已经取得了进展，但有几个障碍阻碍了在确定与T1D风险相关的基因的功能后果方面的进展。这些问题包括与个体基因组区域相关的适度风险，以及不确定这些区域中的哪一个SNP是致病因素，限制了将基因与表型联系起来的机制研究。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，而小鼠模型可能不能反映基因对人类免疫反应的影响。为了克服这些障碍，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T1D中新的遗传变异的功能意义：目标1：我们将利用一种新的遗传学方法来识别T1D中的致病遗传位点，从而识别可以在小鼠和人身上进行有针对性研究的变异。目的2：我们将在小鼠身上建立致病变异的模型，以便研究遗传变异对免疫发育、多细胞群体和体内抗原暴露的反应的影响。目的3：我们将定义与这些致病基因变异相关的功能表型，在患有和不患有T1D的人类中。这些研究将在一定程度上受到小鼠模型研究结果的推动，同时他们也将确定这些模型的发现与人类受试者和T1D的相关性。每个目标都将由各自领域的一名专家指导，该专家在T1D基因-表型研究中的成功合作方面有着良好的记录。这种方法的独特之处在于，尽管每个目标在方法上都是不同的，但本项目每个目标的结果将影响其他目标的方向和实验设计。目标2和目标3的初步研究将侧重于通过遗传学研究工作已经确定的编码变体：PTPN22、SH2B3、TYK2和IFIH1。使用这一综合策略的未来研究将纳入在目标1中进行的b项研究中确定的遗传变异--定义与T1D相关的附加致病遗传变异。这些方法的整合将克服目前限制T1D遗传学进展的障碍，将增强我们对几个与T1D相关的遗传变异的理解，还将为研究其他基因开发一个平台，将促进对T1D疾病发病机制的更好机制理解。

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.