Development of normal and dystrophic canine iPS lines

正常和营养不良犬 iPS 系的发育

基本信息

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
项目类别：
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

项目摘要

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.

狗的大量遗传疾病主要是由于创始人的影响和数百年历史的近亲繁殖习惯所导致的人口瓶颈。其中包括von Willebrand疾病，严重的免疫缺陷障碍，X连锁的Duchenne型肌肉营养不良，丙酮酸激酶缺乏症，肌肉型磷酸果糖激酶缺乏症，血友病和疾病。超过58％的狗遗传疾病（例如杜切尼型肌营养不良症）是由同一基因突变引起的人类疾病的真正同源物。此外，许多现代狗品种中的许多都表现出更复杂的多基因疾病的较高流行率，包括过敏，癌症，失明，心脏病，白内障，癫痫，髋部发育不良和耳聋。由于明显的参数，例如寿命和大小，狗代表了人类疾病的重要模型。在狗中，生理，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，它们提供了一个独特的临床前模型，以测试再生医学和组织工程方法对人类疾病的治疗和治疗的有用性。这些新方法的关键将是使用胚胎干细胞的分化衍生物（ES）。通过相对简单的重新编程步骤，可以从皮肤成纤维细胞中产生自体，多能干细胞（IP）的表现是一个主要的科学进步，它将在许多基础研究和应用临床医学领域产生深远的影响。我们的中心假设是，产生和表征F犬IPS细胞系将加快人类替代组织和器官的发展。为了解决这一假设，提出了以下三个特定目标（1）以从正常和营养不良（GRMD）狗中产生诱导的多能干细胞系（IP）。（2）将对IPS系的基因表达谱图进行表征，并将其与胚泡衍生的犬（3）进行比较，以评估体内和体外的犬类ES和IPS系的多能性。