Genetics of organ-specific lupus disease sequelae

总结/摘要 系统性红斑狼疮（SLE或狼疮）是一种致命的和不可治愈的自身免疫性疾病，其特征是 广泛的炎症和自身抗体的大量产生。临床疾病表现为 症状的异质谱和对器官系统的损害，包括肾脏和心脏。尽管 几十年来对导致SLE发展风险的遗传因素的深入了解， 控制特定疾病表现的遗传机制仍不明确。因此，准确的疾病 预后和有效预防危及生命的器官损伤仍然具有挑战性。值得注意的是， SLE的严重程度和具体器官的受累在不同种族群体之间以及不同的 品系的近交系小鼠，强烈表明遗传线索可能决定疾病的发病机制。然而，在这方面， 与近交系小鼠间杂交相关的有限的基因组变异和有限的重组率 菌株对疾病发病机理的这些遗传驱动因素进行了复杂的剖析。为了更好地模拟人类 疾病，协作交叉是从八个创始人菌株产生的，以捕捉巨大的遗传 小鼠基因组中存在变异。协交系间等位基因组合的多样性 提示比通常在近交系小鼠中观察到的更广泛的疾病表型，从而促进 影响复杂多基因性状的遗传位点的高分辨率作图。 在这个建议中，我们奋进证明协作交叉资源是一个强大的工具，能够 鉴定与SLE临床重要器官特异性表现相关的特异性遗传基因座。我们将应用 我们发现一种尖端的SLE小鼠模型，在不同的SLE患者中， 近交系小鼠SLE样疾病的诱导模型与 协作性交叉资源将促进疾病结局的定性和定量比较， 单个品系的小鼠。在这些小鼠中捕获的遗传变异的广度将使绘制 数量性状基因座，即使是疾病发病机制中的小表型变异。这项研究代表了 有前途的和原始的方法来解决关键的，悬而未决的问题，关于遗传起源的 SLE的异质性器官特异性表现。实验的结果将开启新的 基础和转化研究的途径，确定为风险因素的临床靶向途径， SLE患者出现危及生命的心脏和肾脏病变。此外，这些结果可能会促进 未来还将尝试对SLE的其他异质性表现进行遗传解剖，包括 肌肉骨骼、粘膜皮肤、神经精神和肺部病变。

SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE or lupus) is a deadly and incurable autoimmune disease characterized by widespread inflammation and rampant production of autoantibodies. Clinical disease presents as a heterogeneous spectrum of symptoms and damage to organ systems, including the kidneys and heart. Despite decades of robust insights into the genetic factors contributing to risk for development of SLE, the functional genetic mechanisms governing specific disease manifestations remain undefined. Therefore, accurate disease prognosis and effective prevention of life-threatening organ damage remain challenging. Notably, disease severity and involvement of specific organs in SLE varies amongst different ethnic groups and between disparate strains of inbred mice, strongly suggesting that genetic cues may determine pathogenesis of disease. However, limited genomic variation and restricted recombination rates associated with intercrosses between inbred mouse strains have complicated dissection of these genetic drivers of disease pathogenesis. To better model human disease, the collaborative cross was generated from eight founder strains to capture the tremendous genetic variation present across the mouse genome. The diversity of allele combinations among collaborative cross lines prompts a broader spectrum of disease phenotypes than commonly observed in inbred mice, thereby facilitating high resolution mapping of genetic loci influencing complex polygenic traits. In this proposal, we endeavor to demonstrate that the collaborative cross resource is a powerful tool capable of identifying specific genetic loci linked to clinically important organ-specific manifestations of SLE. We will apply a cutting-edge mouse model of SLE that we find differentially provokes cardiac and renal damage in different inbred mouse strains. The innovative combination of an inducible model of SLE-like disease with the collaborative cross resource will facilitate qualitative and quantitative comparison of disease outcomes among individual strains of mice. The breadth of genetic variation captured in these mice will enable mapping of quantitative trait loci even for small phenotypic variations in disease pathogenesis. This study represents a promising and original approach to address critical, unanswered questions regarding the genetic origins of heterogeneous organ-specific manifestations of SLE. The results of the proposed experiments will open new avenues of basic and translational research into clinically-targetable pathways identified as risk factors for development of life-threatening cardiac and renal pathologies in SLE. Moreover, these results will likely promote additional futures attempts at genetic dissection of other heterogeneous manifestations of SLE, including musculoskeletal, mucocutaneous, neuropsychiatric and pulmonary pathologies.