NIAMS: CORT - Genetic Dissection of SLE--From Mouse to Man

NIAMS：CORT - SLE 的基因剖析——从小鼠到人

• 批准号: 7673593
• 负责人: CHANDRA MOHAN
• 金额: $ 156.83万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673593
• 关键词: NIAMS; CORT; Genetic; Dissection; SLE

DESCRIPTION (provided by applicant): The UTSW-SLE-CORT is focused on translating lessons learned from genetically simplified mouse models to human SLE. Over the past decade, the study of murine lupus has been simplified with the steady replacement of polygenic mouse models of lupus with a series of monogenic mouse models, which greatly simplify the systematic analysis of pathogenic mechanisms leading to SLE. Importantly, these studies have uncovered at least 2 major steps leading to lupus, both genetically encoded. Whereas the first stage is characterized by the presence of anti-nuclear antibodies but not disease, the second stage is marked by the presence of potentially pathogenic autoantibodies and end-organ disease. In the mouse models, the first stage arises as a consequence of polymorphisms in the SLAM family genes, whereas the second stage is driven by genetic loci that encode "hyperactive" pro-inflammatory DCs. Whereas Project 1 focuses on the molecular basis of the 2 stages using mouse models, Projects 2-4 are translational in nature, focusing on identifying similar stages and pathogenic mechanisms in human SLE. The translational Projects are based on 3 novel observations made by the UTSW-SLE-CORT Pis over the past 2 years: (1) We have succeeded in identifying individuals with "early" or "incomplete" lupus (or "ILE"), who fail to meet the minimum requirements for a diagnosis of SLE, reminiscent of some of the mouse models with "early" lupus; (2) We have already established that certain ethnic subsets of their SLE patients show strong association with particular SLAM family genes, notably Ly108/SLAMF6 and CD84, reproducing the observations in mice; (3) It is also evident that human lupus DCs or IMF-treated DCs are better at helping B-cells produce antibodies, again echoing our findings in mice. Based on these exciting leads, the UTSWSLE-CORT proposes to ascertain the role of SLAM family gene polymorphisms and DC help in driving phenotypic maturation in different stages of human SLE. Besides uncovering the pathogenic mechanisms leading to lupus, these studies may also uncover early markers that best predict disease progression in human SLE. Finally, the basic Project (I) and the proposed DC:B-cell studies have the potential to uncover key molecular mediators of disease, which could potentially pave the way towards novel therapeutic opportunities in SLE.

描述（由申请人提供）：UTSW-SLE-CORT专注于将基因简化小鼠模型的经验教训转化为人类SLE。近十年来，随着一系列单基因小鼠模型逐步取代多基因狼疮小鼠模型，小鼠狼疮的研究得到了简化，大大简化了对狼疮致病机制的系统分析。重要的是，这些研究揭示了导致狼疮的至少两个主要步骤，都是遗传编码的。而第一阶段的特点是存在抗核抗体，但没有疾病，第二阶段的特点是存在潜在致病性自身抗体和终末器官疾病。在小鼠模型中，第一阶段是SLAM家族基因多态性的结果，而第二阶段是由编码“过度活跃”促炎dc的遗传位点驱动的。项目1侧重于利用小鼠模型研究这两个阶段的分子基础，而项目2-4本质上是翻译性的，重点是确定人类SLE的相似阶段和致病机制。转化项目基于utsw - slet - cort Pis在过去2年中所做的3项新观察：(1)我们成功地识别了“早期”或“不完全”狼疮（或“ILE”）的个体，这些个体未能满足SLE诊断的最低要求，让人想起一些“早期”狼疮的小鼠模型；(2)我们已经确定SLE患者的某些种族亚群与特定的SLAM家族基因有很强的相关性，特别是Ly108/SLAMF6和CD84，在小鼠中重复了观察结果；(3)同样明显的是，人类狼疮dc或imf治疗的dc在帮助b细胞产生抗体方面更好，这再次与我们在小鼠中的发现相呼应。基于这些令人兴奋的线索，utswslel - cort提出确定SLAM家族基因多态性和DC帮助在人类SLE不同阶段驱动表型成熟的作用。除了揭示导致狼疮的致病机制外，这些研究还可能揭示最能预测人类狼疮疾病进展的早期标志物。最后，基础项目(I)和拟议的DC: b细胞研究有可能发现疾病的关键分子介质，这可能为SLE的新治疗机会铺平道路。