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

描述（由申请人提供）：牙周炎（PD）是牙周组织的炎性疾病。它会导致牙齿失去支撑，如果不及时治疗，会导致牙齿脱落。PD影响30岁以上人口的47.2%。根据世界卫生组织，PD是成年人牙齿脱落的主要原因。虽然细菌生物膜在疾病发病机制中是中心， 宿主反应在PD的进展和严重性中起重要作用。事实上，遗传学研究表明，PD是50%可遗传的。发现与骨质流失相关的遗传特征 在识别易患疾病的个体以及辨别疾病病理生理学基础的信号级联中是必不可少的。由于患者复杂和异质的遗传组成以及难以控制影响疾病的环境因素，临床遗传学研究提出了重大挑战。由于人类和小鼠复合物具有相似的结构，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。我们建议利用杂交小鼠多样性小组（HMDP）进行牙周骨丢失的GWAS。HMDP小组由100个经典和重组近交（RI）小鼠品系组成，选择用于复杂性状的系统遗传分析。在我们的初步研究中，我们采用了实验性牙周骨丢失的小鼠模型，通过将牙龈卟啉单胞菌衍生的LPS注射到上颌磨牙的牙间乳头中。作为原理的证明，我们将该模型应用于29个近交系，包括5个衍生th RI品系的亲本品系。通过显微CT分析，BUB/BnJ是最敏感的菌株LPS诱导的骨丢失相比，最耐药的菌株，SEA/GnJ。基于这些数据，牙周骨丢失的遗传性估计为49%，该值与患者报告的50%的遗传性测量值非常相似。初步数据支持的遗传框架中的显着作用，脂多糖诱导的牙周骨丢失。我们提出了两个具体的目标，以实现我们的目标，以确定遗传变异，有助于牙周骨丢失的严重程度。具体目标1：评估完全HMDP的牙周骨丢失。具体目的2：在HMDP小鼠中进行LPS诱导的牙周骨丢失的GWAS。在进行了证明牙周骨丢失模式存在差异的原理性研究后，我们建议确定数量性状位点;更具体地说，与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研究结果，并扩展到一个系统生物学方法相结合的基因组学，转录组学和蛋白质组学方法，以完全表征骨丢失。最终，我们的研究将有助于预测患者的遗传易感性PD和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.