Development of normal and dystrophic canine iPS lines

正常和营养不良犬 iPS 系的发育

• 批准号: 7845006
• 负责人: COLIN Edward BISHOP
• 金额: $ 18.32万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845006
• 关键词: Address; Area; Autologous; Basic Science; Blindness; Breeding; Canis familiaris; Cataract; Cell Line; Clinical; Clinical Medicine; Complex; Development; Disease; Duchenne muscular dystrophy; Dysplasia; Epilepsy; Fibroblasts; Founder Effect; Gene Expression; Generations; Genes; Heart Diseases; Hemophilia A; Hereditary Disease; High Prevalence; Hip region structure; Homologous Gene; Human; Hypersensitivity; Immunologic Deficiency Syndromes; In Vitro; Inbreeding; Link; Longevity; Malignant Neoplasms; Modeling; Molecular Profiling; Muscle; Muscular Dystrophies; Narcolepsy; Organ; Physiology; Pluripotent Stem Cells; Population; Pre-Clinical Model; Regenerative Medicine; Scientific Advances and Accomplishments; Severe Combined Immunodeficiency; Skin; Testing; Tissue Engineering; Tissues; blastocyst; deafness; disease-causing mutation; embryonic stem cell; human disease; in vivo; induced pluripotent stem cell; mouse model; novel strategies; pluripotency; pyruvate kinase deficiency; response; von Willebrand Disease

A large number of genetic diseases occur in dogs mainly due to founder effects and population bottlenecks resulting from centuries-old inbreeding practices. These include von Willebrand disease, severe combined immunodeficiency disorder, X-linked Duchenne type muscular dystrophy, pyruvate kinase deficiency, muscle type phosphofructokinase deficiency, hemophilia and narcolepsy. More than fifty-eight percent of dog genetic diseases, such as Duchenne-type muscular dystrophy, are true homologues of human diseases caused by mutations in the same gene. In addition, many of the more than 400 modern dog breeds show a high prevalence of more complex multigenic diseases, including allergies, cancers, blindness, heart disease, cataracts, epilepsy, hip dysplasia and deafness. Because of obvious parameters such as lifespan and size, dogs represent an important model for human disease. In dogs, the physiology, disease presentation and clinical response often parallels that of the human more closely than the corresponding mouse model. They therefore provide a unique preclinical model to test the usefulness of regenerative medicine and tissue engineering approaches to the treatment and cure of Human disease. Pivotal to these new approaches will be the use of the differentiated derivatives of embryonic stem cells (ES). The recent demonstration that is possible to generate autologous, pluripotent stem cells (iPS) from skin fibroblasts, by relatively simple reprogramming steps is a major scientific advance which will have profound ramifications in many areas of basic research and applied clinical medicine. It is our central hypothesis that the generation and characterization f canine iPS cell lines will hasten the development of replacement tissues and organs in human. In order to address this hypothesis the following three specific aims are proposed (1) To generate induced pluripotent stem cell lines (iPS) from normal and dystrophic (GRMD) dogs. (2) Gene expression profiles of iPS lines will be characterized and compared to a blastocyst derived canine (3) To assess the pluripotency of canine ES and iPS lines in vivo and in vitro.

狗身上出现大量遗传疾病，主要是由于数百年近亲繁殖造成的创始人效应和种群瓶颈。 这些包括冯·维勒布兰德病、严重联合免疫缺陷病、X连锁杜氏型肌营养不良症、丙酮酸激酶缺乏症、肌肉型磷酸果糖激酶缺乏症、血友病和发作性睡病。 超过百分之五十八的狗遗传疾病，例如杜兴型肌营养不良症，是由同一基因突变引起的人类疾病的真正同源物。 此外，400多种现代犬种中的许多都表现出更复杂的多基因疾病的高患病率，包括过敏、癌症、失明、心脏病、白内障、癫痫、髋关节发育不良和耳聋。 由于寿命和体型等明显参数，狗代表了人类疾病的重要模型。 在狗中，其生理学、疾病表现和临床反应通常比相应的小鼠模型更接近人类。 因此，他们提供了一个独特的临床前模型来测试再生医学和组织工程方法治疗和治愈人类疾病的有效性。 这些新方法的关键是胚胎干细胞（ES）分化衍生物的使用。 最近的研究表明，可以通过相对简单的重编程步骤从皮肤成纤维细胞产生自体多能干细胞（iPS），这是一项重大科学进步，将对基础研究和应用临床医学的许多领域产生深远的影响。 我们的中心假设是，犬 iPS 细胞系的产生和表征将加速人类替代组织和器官的发育。 为了解决这一假设，提出了以下三个具体目标（1）从正常和营养不良（GRMD）狗中产生诱导多能干细胞系（iPS）。 (2) 对 iPS 系的基因表达谱进行表征，并与囊胚来源的犬进行比较。 (3) 评估犬 ES 和 iPS 系在体内和体外的多能性。