Genetic Regulation of interferon Alpha in Human Lupus

描述（由申请人提供）：干扰素α（IFN-α）是一种细胞因子，对系统性红斑狼疮（SLE）的发病机制至关重要。我们小组以前的工作表明，IFN-α活性增加是一种遗传性SLE风险因素，但这种风险因素的遗传调控在很大程度上是未知的。我们假设许多遗传风险因素导致IFN-α通路的失调，导致IFN-α信号传导增加和随后的SLE风险。在这个提议中，我们将研究IFN-α通路中候选基因的功能意义。我们将测量与SLE相关的基因对SLE患者体内血清IFN-α活性和下游IFN-α诱导的基因表达的贡献。我们还将在我们当地SLE患者队列的全基因组研究中验证与血清IFN-α活性相关的许多新的候选基因座作为大型独立队列中的SLE风险基因座。然后将以与上述类似的方式在IFN-α途径内功能性地表征经验证的新候选物，并且我们预期将出现SLE患者体内IFN-α调节的遗传模型。短期职业目标包括完成和出版我们在提案中提出的初步研究，以及统计遗传学课程计划。数据将定期在实验室会议和粉笔会谈中展示，我将每周与我的两位导师会面。长期职业目标包括描述提案中描述的新候选人的特征，以及提交独立的资助者发起的赠款，例如基于这些项目中产生的初步数据的NIH R 01。此外，我将参加芝加哥大学丰富的科学环境，参加由流变学科、遗传医学科和免疫学委员会主办的研讨会和会议。K奖机制的支持将使我能够积极追求本提案中概述的科学和教育目标。相关性（参见说明）：我们将使用遗传和功能分析相结合，以确定在SLE患者体内引起IFN-α通路失调的重要遗传因素。这项工作具有直接的临床相关性，因为靶向IFN-α途径的药物目前在SLE药物开发中是高度优先的。我们的研究结果可以允许针对人类SLE中IFN-α通路的更特异和个性化的治疗，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.