Genetic contribution to degenerative tendon and ligament rupture in Equus ferus caballus

项目摘要/摘要 在理解基因对特定部位自发的贡献方面存在着根本的差距 肌腱/韧带断裂。跟腱、肩袖和前十字韧带常有病变。 这种情况代表慢性退行性肌腱/韧带的急性损伤。继续存在 这一知识鸿沟代表着一个重要的问题，因为在它被填补之前，理解 导致自发性肌腱/韧带断裂风险的遗传变异数量将在很大程度上保持不变 令人费解。长期目标是发现自发性肌腱/韧带断裂的原因遗传 变种。我们的总体目标是通过全面的基因组解剖来发现候选的遗传变异 马退行性悬韧带桥炎(DSLD)是一种优秀的自发性大动物模型 肌腱/韧带断裂。马的基因组结构通过以下方式增加了SNP关联的力量 随着连锁不平衡的增加，品种内全基因组关联研究(GWAS)相对于 人类基因组。中心假设是DSLD有一个重要的遗传成分，即孟德尔基因。 这一假设是根据申请人实验室提供的初步数据提出的。 拟议研究的基本原理是，支持DSLD和DSLD的基因组结构知识 在马模型中发现候选遗传变异将使新的创新方法成为可能 预防和治疗人体自发性肌腱/韧带断裂并提供新的治疗方法 模特。在强大的初步数据的指导下，这一假设将通过追求两个具体目标来检验：1)使用 RNA测序(RNA-Seq)以确定DSLD破裂组织中差异表达的基因和2)发现 DSLD破裂候选遗传变异的Gwas分析及随后的全基因组区域分析 序列(WGS)数据。在第一个目标下，差异表达基因将通过分析 疾病组织中的转录组，以评估生物网络的干扰。在第二个目标下， 基因组单核苷酸多态(SNPs)将被用于发现GWAs。我们将测试我们的工作 假设DSLD是一种孟德尔病，可由一种遗传变异解释，该变异在 受DSLD影响的品种。共有的变异更有可能与人类疾病密切相关。这项工作是 这是一种创新，因为它通过研究马的模型与通常的GWAS方法不同。新的研究视野 预计将会因此实现。这项拟议的研究意义重大，因为预计它将 发现一种新的自发性肌腱/韧带断裂候选遗传变异及其相关生物 小路。这项工作将有助于阐明自发性心脏病发病机制中受到干扰的常见途径。 肌腱/韧带断裂。在马模型中发现的大效应变异将提供新的靶点 人类患者的预防性或治疗性管理。

Project Summary/Abstract There is a fundamental gap in understanding the genetic contribution to site-specific spontaneous tendon/ligament rupture. The Achilles tendon, rotator cuff, and anterior cruciate ligament are often diseased. Such conditions represent acute damage of a chronically degenerated tendon/ligament. Continued existence of this knowledge gap represents an important problem because, until it is filled, understanding how the large number of genetic variants that contribute to risk of spontaneous tendon/ligament rupture will remain largely incomprehensible. The long-term goal is to discover spontaneous tendon/ligament rupture causal genetic variants. Our overall objective is to discover candidate genetic variants by comprehensive genomic dissection of equine degenerative suspensory ligament desmitis (DSLD), an excellent large animal model of spontaneous tendon/ligament rupture. The genomic architecture of horses acts to increase Power for SNP association by within-breed genome-wide association study (GWAS) as linkage disequilibrium is increased relative to the human genome. The central hypothesis is that DSLD has an important genetic component that is Mendelian. This hypothesis has been formulated on the basis of preliminary data produced in the applicant’s laboratory. The rationale for the proposed research is that knowledge of the genomic architecture underpinning DSLD and discovery of candidate genetic variants in the equine model will enable new and innovative approaches to prevention and treatment of human spontaneous tendon/ligament rupture and also provide a new treatment model. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Use RNA sequencing (RNA-Seq) to identify differentially expressed genes in ruptured DSLD tissue and 2) Discover DSLD rupture candidate genetic variants by GWAS and subsequent region-based analysis of whole genome sequence (WGS) data. Under the first aim, differentially expressed genes will be identified by analyzing the transcriptome in diseased tissue to assess disturbances to biological networks. Under the second aim, genomic single nucleotide polymorphisms (SNPs) will be used for discovery GWAS. We will test our working hypothesis that DSLD is a Mendelian disease that is explained by a genetic variant that is shared across DSLD-affected breeds. A shared variant is more likely to be strongly linked to human disease. The work is innovative as it departs from the usual GWAS approach by studying an equine model. New research horizons are expected to be attainable as a result. The proposed research is significant, because it is expected to discover a novel spontaneous tendon/ligament rupture candidate genetic variant and the associated biological pathways. This work will help clarify common pathways that are disturbed in the pathogenesis of spontaneous tendon/ligament rupture. Large effect variants identified in the equine model will provide new targets for preventative or therapeutic management of human patients.