Screen for Identification of Important Human Birth Defect Models in Swine

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来的结果。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和现成的大型动物模型来开发和测试治疗。本提案旨在确定自然发生的遗传猪模型的特定出生缺陷，需要大型动物模型。在一个小的试点筛选中，我们已经证明这种方法是可行的，并且很可能是成功的，因为在相关的猪群中已经发现了潜在的梗阻性尿病表型。在目标1中，我们建议在猪中进行大规模筛选，以确定具有特定结构性出生缺陷复发的群体。我们提出确定的出生缺陷在猪中已经有过报道，包括先天性膈疝（CDH）、先天性心脏病、脊髓脊膜膨出、梗阻性尿病和口面裂。在Aim 2中，鉴定出先天性缺陷的人群将用于确定特定表型是否适合人类疾病研究的模型。还将确定遗传能力和遗传模式，并从受影响人群中提取和储存DNA，以供未来的遗传研究。长期目标是扩大已确定的具有高遗传性和与人类疾病高度相关的特定模型，以便向研究界分发。这些工具的可用性将大大加强实验性疗法对人类的转化，并对人类疾病产生直接和迅速的影响。

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.