Genetics of organ-specific lupus disease sequelae

摘要/摘要 系统性红斑狼疮(SLE或狼疮)是一种致命的、不可治愈的自身免疫性疾病，其特征是 广泛的炎症和猖獗的自身抗体产生。临床疾病表现为 不同的症状和器官系统的损害，包括肾脏和心脏。尽管 几十年来，人们对导致系统性红斑狼疮(SLE)发病风险的遗传因素有了强有力的见解 控制特定疾病表现的遗传机制仍不清楚。因此，精准的疾病 威胁生命的器官损害的预测和有效预防仍然具有挑战性。值得注意的是，疾病 系统性红斑狼疮特定器官的严重程度和受累程度在不同种族和不同种族之间存在差异 近亲交配小鼠的品系，强烈表明遗传线索可能决定疾病的发病机制。然而， 与近交系小鼠杂交相关的有限基因组变异和有限重组率 菌株对这些疾病发病的遗传驱动因素进行了复杂的剖析。为了更好地为人类建模 疾病，协作杂交是由八个创始人菌株产生的，以捕获巨大的遗传 小鼠基因组中存在变异。协同杂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座位的高分辨率定位。 在这个建议中，我们努力证明协作交叉资源是一个强大的工具，能够 确定与系统性红斑狼疮临床上重要的器官特异性表现相关的特定遗传位点。我们会申请 我们发现一种SLE的尖端小鼠模型在不同的不同程度上引起心脏和肾脏损害 近交系小鼠品系。系统性红斑狼疮样疾病的可诱导模型与 协作的交叉资源将促进以下疾病结果的定性和定量比较 个别品系的小鼠。在这些小鼠身上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微小表型变异。这项研究代表了一项 有希望的原创方法，以解决关键的，悬而未决的问题，关于遗传起源 系统性红斑狼疮的不同器官特异性表现。拟议中的实验结果将开启新的 基础研究和转化性研究的途径--临床靶向途径被确定为高血压的危险因素 系统性红斑狼疮患者危及生命的心脏和肾脏病理的发展。此外，这些结果可能会促进 其他期货尝试对SLE的其他异质性表现进行遗传解剖，包括 肌肉骨骼、皮肤粘膜、神经精神病学和肺部病理学。

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.