CANINE MODELS OF FAMILIAL DILATED CARDIOMYOPATHY

家族性扩张型心肌病的犬模型

• 批准号: 2451975
• 负责人: KATHRYN M MEURS
• 金额: $ 8.54万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-18 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2451975
• 关键词: disease /disorder model; dogs; dystrophin; echocardiography; electrocardiography; gene mutation; genetic disorder; genetic disorder diagnosis; linkage mapping; molecular cloning; molecular genetics; molecular pathology; muscular dystrophy; myocardium disorder; open reading frames; phenotype; polymerase chain reaction; restriction fragment length polymorphism; southern blotting

Dilated cardiomyopathy(DCM) is a primary heart muscle disease characterized by systolic dysfunction and ventricular dilatation; it occurs naturally in many species.(1-3) Approximately 20% of human DCM appears to be of familial origin, and the trait may be inherited in an autosomal (dominant or recessive), X-linked, or mitochondrial pattern.(4,5) Canine models of familial DCM also exists. Greater than 50% of dogs diagnosed as having DCM are Doberman pinschers and they have close similarities to familial DCM in humans. (6-8) Golden retrievers are also known to have familial DCM and sometimes have DCM associated with a muscular dystrophy similar to Duchenne muscular dystrophy (DMD) in humans.(9-12) In addition to DCM, dystrophin abnormalities have been shown in some cases. (13-15) We believe that a natural animal model of familial DCM could provide opportunities to study at least one cause of DCM at the molecular level and provide a candidate gene model for human disease. Pedigrees from Doberman pinschers and golden retrievers with DCM have been collected; the phenotypes of affected and unaffected individuals were characterized. Blood samples have also been obtained from affected and unaffected family members to develop lymphoblastoid cell lines as an immortalized.source of DNA, and for DNA isolation. Those dogs succumbing to DCM will be autopsied; cardiac and skeletal muscle samples have been obtained (fresh frozen when possible, or formalin-fixed). Doberman pinscher and golden retriever DNA isolated from individuals (blood, tissue) will be subjected to linkage analysis to map the chromosomal locus responsible for DCM and the region will be cloned to isolate and identify the responsible gene prior to performing mutation analysis. Also, samples will be analyzed for dystrophin deletions by multiplex PCR and other mutations.(16,17) This study will ultimately provide a natural animal model in which to study familial DCM at a molecular level and potentially provide a candidate gene(s) for evaluation in humans with this form of cardiomyopathy, as well as potentially improving the knowledge of DCM in DMD and X-linked DCM, human diseases due to dystrophin abnormalities.(18)

扩张型心肌病（DCM）是一种原发性心肌疾病 以收缩功能障碍和心室扩张为特征；它 许多物种中自然发生。(1-3) 约 20% 的人类 DCM 似乎具有家族起源，并且该特征可能会遗传 常染色体（显性或隐性）、X 连锁或线粒体 (4,5) 家族性 DCM 的犬模型也存在。大于50% 被诊断患有 DCM 的狗是杜宾犬，并且它们与 与人类家族性 DCM 相似。 (6-8)金毛也 已知患有家族性 DCM，有时患有与某种疾病相关的 DCM 与杜氏肌营养不良症 (DMD) 相似的肌营养不良症 人类。(9-12) 除了扩张型心肌病之外，肌营养不良蛋白异常也已被证实 在某些情况下。 (13-15) 我们相信，家族性的自然动物模型 DCM 可以提供研究至少一种 DCM 病因的机会 分子水平并为人类疾病提供候选基因模型。 患有 DCM 的杜宾犬和金毛猎犬的血统书 集;受影响和未受影响个体的表型是 特点。还从受影响的人和 未受影响的家庭成员开发淋巴母细胞系作为 永生化。DNA 来源，以及用于 DNA 分离。那些狗屈服了 将向 DCM 进行尸检；心肌和骨骼肌样本 获得（如果可能的话新鲜冷冻，或福尔马林固定）。杜宾犬 从个体（血液、 组织）将进行连锁分析以绘制染色体位点图 负责 DCM 的区域将被克隆以进行分离和识别 在进行突变分析之前确定负责基因。另外，样品 将通过多重 PCR 和其他方法分析肌营养不良蛋白缺失 突变。(16,17)这项研究最终将提供一种天然动物 在分子水平上研究家族性 DCM 的模型，并可能 提供候选基因用于以这种形式对人类进行评估 心肌病，以及潜在地提高 DCM 的知识 DMD 和 X 连锁 DCM，由肌营养不良蛋白异常引起的人类疾病。(18)