Mouse Genome-Wide Association Studies in LPS-Induced Bone Loss

描述(申请人提供)：牙周炎(PD)是一种牙周组织的炎症性疾病。它会导致牙齿支撑力的丧失，如果不进行治疗，可能会导致牙齿脱落。帕金森病影响47.2%的30岁以上人口。根据世界卫生组织的说法，帕金森病是成年人牙齿脱落的主要原因。尽管细菌生物膜在疾病发病机制中处于核心地位， 宿主反应在帕金森病的进展和严重程度中起重要作用。的确，遗传研究表明帕金森病有50%是可遗传的。发现与骨质流失相关的遗传特征 在识别易患这种疾病的个体以及识别构成疾病病理生理学基础的信号级联过程中至关重要。由于患者的复杂和异质性的基因构成，以及难以控制影响疾病的环境因素，临床遗传学研究构成了巨大的挑战。由于人类和小鼠复合体具有相似的结构、功能和遗传特征，因此小鼠模型是全基因组关联研究(GWAS)的理想模型，其中控制遗传和环境框架至关重要。我们建议使用杂交小鼠多样性小组(HMDP)进行牙周骨丢失的GWA。HMDP小组由100个经典和重组近交系(RI)小鼠品系组成，这些品系被选作复杂性状的系统遗传分析。在我们的初步研究中，我们采用了一种实验性牙周骨丢失的小鼠模型，方法是在上颌磨牙牙间乳头内注射牙龈假单胞菌来源的脂多糖。作为原理的证明，我们将该模型应用于29个近交系菌株，其中包括5个衍生TH RI菌株的亲本菌株。通过显微CT分析，与抗性最强的SEA/GNJ相比，BUB/BNJ是最易受内毒素诱导的骨丢失的菌株。基于这些数据，牙周骨丢失的遗传度估计为49%，这个值与报告的患者遗传度测量的50%非常相似。初步数据支持遗传框架在脂多糖诱导的牙周骨丢失中的重要作用。我们提出了两个具体的目标来实现我们的目标，以确定导致牙周骨丢失严重程度的基因变异。具体目标1：评估完全性HMDP的牙周骨丢失。具体目的2：建立脂多糖诱导的HMDP小鼠牙周骨丢失模型。在进行了证明牙周骨丢失模式不同的原理研究后，我们建议确定数量性状基因座；更具体地说，识别与TE-LPS诱导的骨丢失相关的基因。在未来的研究中，我们打算验证我们的发现，并扩展到结合基因组、转录组和蛋白质组方法的系统生物学方法，以完全描述骨丢失的特征。最终，我们的研究将有助于预测遗传倾向于帕金森病的患者，并确定疾病易感性的生物学基础。

DESCRIPTION (provided by applicant): Periodontitis (PD) is an inflammatory disease of the periodontal tissues. It results in the loss of tooth support and, if left untreated it can lead to ooth loss. PD affects 47.2% of the population over the age of 30. According to the WHO, PD is a major cause of tooth loss in adults. Although bacterial biofilm is central in disease pathogenesis, host response plays an important role in the progression and severity of PD. Indeed, genetic studies indicate that PD is 50% heritable. Discovering genetic traits that correlate with bone loss is essential in identifying individuals prone to the disease as well as in discerning signaling cascades that underlie disease pathophysiology. Clinical genetic studies pose significant challenges due to complex and heterogeneous genetic makeup of patients and difficulties in controlling environmental factors that influence the disease. Since human and murine complexes share similar structural, functional and genetic traits, a mouse model is ideal for genome-wide association studies (GWAS) where controlling the genetic and environmental framework is critical. We propose to perform GWAS of periodontal bone loss utilizing the Hybrid Mouse Diversity Panel (HMDP). The HMDP panel consists of 100 classic and recombinant inbred (RI) mouse strains selected for systematic genetic analyses of complex traits. In our preliminary studies, we employed a mouse model of experimental periodontal bone loss by injecting P. gingivalis-derived LPS in the interdental papillae of maxillary molars. As proof of principle, we applied this model to 29 inbred strains, including 5 parental strains that derived th RI strains. Through micro-CT analysis, BUB/BnJ was the most susceptible strain to LPS-induced bone loss compared to the most resistant strain, SEA/GnJ. Based on these data, heritability estimate for periodontal bone loss was 49%, a value that closely resembles heritability measurements of 50% reported for patients. Preliminary data support a significant role of the genetic framework in LPS-induced periodontal bone loss. We propose two Specific Aims to achieve our objective to identify genetic variants that contribute to the severity of periodontal bone loss. Specific Aim 1: To assess periodontal bone loss for the complete HMDP. Specific Aim 2: To perform GWAS of LPS-induced periodontal bone loss in HMDP mice. Having performed proof of principle studies that demonstrate a difference in the periodontal bone loss pattern, we propose to identify quantitative trait loci; more specifically, genes associated with te LPS-induced bone loss. In future studies, we intend to validate our findings and expand to a systems biology approach combining genomic, transcriptomic and proteomic methodologies to completely characterize the bone loss. Ultimately, our studies will contribute in predicting patients genetically predisposed to PD and in identifying the biological basis of disease susceptibility.