Genetic Regulation of interferon Alpha in Human Lupus

描述(申请人提供)：干扰素α(干扰素-a)是一种细胞因子，在系统性红斑狼疮(SLE)的发病机制中至关重要。我们小组以前的工作表明，干扰素-α活性增加是一种可遗传的系统性红斑狼疮风险因素，然而，这种风险因素的遗传调控在很大程度上是未知的。我们假设一些遗传风险因素导致干扰素-a途径的失调，导致干扰素-a信号的增加和随后的系统性红斑狼疮的风险。在这项建议中，我们将研究干扰素-a途径中候选基因的功能意义。我们将测量SLE相关基因对SLE患者体内血清干扰素-α活性和干扰素-α下游诱导基因表达的贡献。我们还将在一项对本地SLE患者队列进行的全基因组研究中，验证一些与血清干扰素-α活性相关的新的候选基因座，作为大型独立队列中的SLE风险基因座。经过验证的新候选者将以类似于上述的方式在干扰素-a途径中进行功能表征，我们预计体内SLE患者中的干扰素-a调节的遗传模型将会出现。短期的职业目标包括完成和发表我们在提案中提出的初步研究，以及统计遗传学的课程计划。数据将定期在实验室会议和粉笔讲座中展示，我每周都会与我的两位导师会面。长期的职业目标包括对提案中描述的新候选人的特征，以及根据这些项目产生的初步数据提交独立调查人员发起的赠款，如NIH R01。此外，我还将参加芝加哥大学丰富的科学环境，参加风湿病学部、遗传医学部和免疫学委员会主办的研讨会和会议。来自K奖励机制的支持将使我能够积极地追求这项提议中概述的科学和教育目标。相关性(参见说明书)：我们将结合遗传和功能分析来确定导致SLE患者体内干扰素-a途径失调的重要遗传因素。这项工作具有直接的临床意义，因为针对干扰素-a途径的药物目前在系统性红斑狼疮药物开发中处于高度优先的地位。我们的发现可能允许针对人类SLE中的干扰素-a途径进行更具体和个性化的治疗，并可能提出预防策略。

DESCRIPTION (provided by applicant): Interferon alpha (IFN-a) is a cytokine which is critically important to the pathogenesis of systemic lupus erythematosus (SLE). Previous work from our group suggests that increased IFN-a activity is a heritable SLE risk factor, however the genetic regulation of this risk factor is largely unknown. We hypothesize that a number genetic risk factors result in dysregulation of the IFN-a pathway, causing increased IFN-a signaling and subsequent risk of SLE. In this proposal, we will examine the functional significance of candidate genes within the IFN-a pathway. We will measure the contribution of genes associated with SLE to in vivo serum IFN-a activity and downstream IFN-a- induced gene expression in SLE patients. We will also validate a number of novel candidate loci which were associated with serum IFN-a activity in a genome-wide study of our local SLE patient cohort as SLE risk loci in a large independent cohort. Novel candidates which are validated will then be characterized functionally within the IFN-a pathway in a similar manner as above, and we expect that a genetic model of IFN-a regulation in SLE patients in vivo will emerge. Short term career goals include the completion and publication of the preliminary studies which we present in the proposal, as well as a program of coursework in statistical genetics. Data will be presented regularly in lab meetings and chalk talks, and I will meet weekly with both of my mentors. Long term career goals include the characterizing the novel candidates described in the proposal, and submission of independent investigator-initiated grants such as the NIH R01 based on preliminary data generated in these projects. Additionally, I will participate in the rich scientific environment at University of Chicago, attending seminars and conferences hosted by the Section of Rheumatology, the Section of Genetic Medicine, and the Committee on Immunology. Support from the K Award mechanism will enable me to aggressively pursue both the scientific and educational aims outlined in this proposal. RELEVANCE (See instructions): We will use a combination of genetic and functional analyses to identify the important genetic elements causing IFN-a pathway dysregulation in vivo in SLE patients. This work has direct clinical relevance, as agents targeting the IFN-a pathway are currently a high priority in SLE drug development. Our findings could allow for more specific and personalized therapies targeting the IFN-a pathway in human SLE, and may suggest preventive strategies.