Screen for Identification of Important Human Birth Defect Models in Swine

猪重要人类出生缺陷模型的筛选鉴定

• 批准号: 7922757
• 负责人: KATE G. ACKERMAN
• 金额: $ 14.86万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922757
• 关键词: Affect; Anatomy; Animal Model; Biomedical Research; Childhood; Cleft Lip; Collection; Common Ventricle; Communities; Congenital Abnormality; Congenital diaphragmatic hernia; DNA; Defect; Disease; Disease Progression; Early treatment; Family; Family suidae; Fetus; Future; Genetic; Goals; Heritability; Human; Human Pathology; Inheritance Patterns; Intervention; Investigational Therapies; Lesion; Maps; Meningomyelocele; Modeling; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Palate; Pediatric Surgical Procedures; Perinatal; Phenotype; Physiology; Population; Recurrence; Reporting; Research; Science; Source; Testing; Tissues; Translations; congenital heart disorder; fetal; fetus surgery; genetic pedigree; human disease; improved; mortality; neonate; novel strategies; orofacial; prevent; tool; trait; treatment strategy; urinary tract obstruction

DESCRIPTION (provided by applicant): Structural birth defects are a devastating cause of fetal, perinatal, and pediatric loss and contribute to a great deal of long term morbidity. Some common congenital defects may be amenable to new treatment strategies that start in the fetus as early treatment may modulate later outcomes. Although treatment strategies including fetal surgery have made huge advances over the past decade, a major limitation continues to be the lack of suitable and readily available large animal models to develop and test therapy. This proposal seeks to identify naturally occurring genetic swine models for specific birth defects for which large animal models are needed. In a small pilot screen, we have shown that this approach is feasible and likely to be successful as a potential obstructive uropathy phenotype has already been discovered in a related population of swine. In Aim 1, we propose to conduct a large scale screen in swine to identify populations with recurrence of specific structural birth defects. The birth defects that we propose to identify have previously been reported in swine and include congenital diaphragmatic hernia (CDH), congenital heart disease, myelomeningocele, obstructive uropathy, and orofacial clefting. In Aim 2, populations identified with congenital defects will be used to determine whether the specific phenotypes would make suitable models for human disease research. The heritability and patterns of inheritance will also be determined, and DNA will be extracted and stored from affected populations for future genetic studies. The long term goal is for the specific identified models with high heritability and high relevance to human disease to be expanded for distribution to the research community. The availability of these tools would greatly enhance the translation of experimental therapies to the human and have a direct and rapid impact on human disease. PUBLIC HEALTH RELEVANCE: In this proposal, we will screen piglets that die of "natural causes" to determine if specific herds are carrying genetic birth defects that could serve as important models of human disease. The birth defects that will be screened are: congenital diaphragmatic hernia (CDH), congenital heart disease, myelomeningocele, obstructive uropathy, and orofacial clefting. Our hope is that once they are identified, those affected pig families (carriers) could then be used to provide the research community with important models to test new therapies for the human fetus or neonate. This would potentially have a huge and rapid impact on treatment for these disorders.

描述（由申请人提供）：结构性出生缺陷是胎儿、围产期和儿科损失的破坏性原因，并导致大量长期发病率。一些常见的先天性缺陷可能适用于从胎儿开始的新治疗策略，因为早期治疗可能会调节后期结果。尽管包括胎儿手术在内的治疗策略在过去十年中取得了巨大的进步，但一个主要的限制仍然是缺乏合适的和现成的大型动物模型来开发和测试治疗。该提案旨在确定需要大型动物模型的特定出生缺陷的自然发生的遗传猪模型。在一个小的试点筛选中，我们已经表明，这种方法是可行的，并可能是成功的，因为一个潜在的梗阻性尿路病表型已经在相关的猪群中发现。在目标1中，我们建议在猪中进行大规模筛选，以识别具有特定结构性出生缺陷复发的群体。我们提出要识别的出生缺陷先前已在猪中报告，包括先天性腹股沟疝（CDH）、先天性心脏病、脊髓脊膜膨出、阻塞性尿路病和口面裂。在目标2中，将使用经鉴定具有先天性缺陷的群体来确定特定表型是否可用于人类疾病研究的合适模型。还将确定遗传性和遗传模式，并将从受影响人口中提取和储存DNA，供今后进行遗传研究。长期目标是将具有高遗传性和与人类疾病高度相关性的特定识别模型扩展到研究社区。这些工具的可用性将大大提高实验疗法对人类的转化，并对人类疾病产生直接和快速的影响。 公共卫生关系：在这项提案中，我们将筛选死于“自然原因”的仔猪，以确定特定的猪群是否携带遗传性出生缺陷，这些缺陷可能成为人类疾病的重要模型。筛查的出生缺陷包括：先天性腹股沟疝（CDH）、先天性心脏病、脊髓脊膜膨出、梗阻性尿路病和口面裂。我们的希望是，一旦它们被识别出来，那些受影响的猪家族（携带者）就可以被用来为研究界提供重要的模型，以测试人类胎儿或新生儿的新疗法。这可能会对这些疾病的治疗产生巨大而迅速的影响。