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毁灭性原因，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影响后来的结果。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的和容易获得的大动物模型来开发和测试治疗方法。这项建议旨在为需要大型动物模型的特定出生缺陷确定自然产生的遗传猪模型。在一个小型的试验性筛选中，我们已经证明了这种方法是可行的，而且很可能成功，因为已经在相关的猪群体中发现了一种潜在的梗阻性尿路病表型。在目标1中，我们建议对猪进行大规模筛查，以确定特定结构性出生缺陷复发的人群。我们建议确定的出生缺陷以前在猪中被报道过，包括先天性横隔膜疝气(CDH)、先天性心脏病、脊髓脊膜膨出、梗阻性尿病和口面部裂伤。在目标2中，被确认患有先天性缺陷的人群将被用来确定特定的表型是否会成为适合人类疾病研究的模型。还将确定遗传力和遗传模式，并将从受影响的人群中提取和存储DNA，以供未来的遗传学研究。长期目标是将具有高遗传力和与人类疾病高度相关的特定识别模型扩大到研究界。这些工具的提供将极大地促进实验性疗法对人类的转化，并对人类疾病产生直接和快速的影响。 与公共卫生相关：在这项提案中，我们将对死于“自然原因”的仔猪进行筛查，以确定特定的猪群是否携带可能作为人类疾病重要模型的遗传出生缺陷。将进行筛查的出生缺陷包括：先天性横隔膜疝气(CDH)、先天性心脏病、脊髓脊膜膨出、梗阻性尿路疾病和口腔裂伤。我们希望，一旦他们被确认，这些受影响的猪家庭(携带者)然后可以被用来为研究界提供重要的模型，以测试针对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。

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.