Mechanism of a novel cause of spina bifida

脊柱裂的新病因机制

基本信息

批准号：
7820102
负责人：
JOHN A KLINGENSMITH
金额：
$ 26.47万
依托单位：
DUKE UNIVERSITY
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：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7820102
关键词：
Ablation Accounting Address Adhesions Affect Alleles Animal Husbandry Applications Grants Area Biological Assay Biological Models Birth Cell Adhesion Cell Adhesion Molecules Cell Death Cells Cellular Assay Clinical Communities Complement Congenital Abnormality Data Development Diagnostic Dorsal Dose Elements Embryo Employment Epidemiology Etiology Failure Folate Genes Genetic Genetic Crosses Homozygote Hour Human Individual Infant Inositol Knock-out Knowledge Lead Life Lumbar Regions Lumbar spinal cord structure Maintenance Modeling Molecular Morbidity - disease rate Mouse Strains Mus Mutant Strains Mice N-Cadherin National Institute of Neurological Disorders and Stroke Nerve Nervous system structure Neural Crest Neural Fold Neural Tube Defects Neural tube Neurologic Pathogenesis Pathway interactions Phenocopy Phenotype Research Resistance Signal Transduction Spinal Cord Spinal Dysraphism Supplementation Tail Testing Therapeutic Tissues Translational Research Tube Work base cost disability in utero inhibitor/antagonist life time cost malformation man mortality mouse model mutant nervous system development nervous system disorder novel prevent public health relevance relating to nervous system repaired small molecule social spine bone structure

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science, and the specific Challenge Topic, 15-NS-106: Identifying mechanisms that underlie nervous system development and function. This Challenge solicits mechanistic studies that elucidate principles of nervous system formation, as well as analyses of how normal mechanisms are perturbed in neurological disease. Spina bifida is one of the most common structural malformations in man; despite its high mortality and morbidity, the etiological causes of spina bifida remain poorly understood. We propose a mechanistic analysis of the causes of lumbar spina bifida in Noggin mutant mice. In contrast to virtually all other mouse strains with neural tube defects, the spina bifida phenotype in Noggin does not occur through a failure of the dorsal neural folds to close into a tube. Rather, a day or so after closure the lumbar spinal cord reopens dorsally in isolated regions along the midline. This results in a lumbar spina bifida phenotype. This mutant represents a novel mouse model for an unexplored mechanism of spina bifida that is likely to be more relevant to pathogenesis of some human cases of spina bifida than models in which the neural tube fails to close. We use tissue-specific gene ablation to determine the individual tissue requirements Noggin for maintenance of neurulation. Our preliminary data indicate that Noggin promotes adhesion of neural tube cells to cell adhesion molecules such as N-cadherin. Our overall hypothesis is that Noggin is required in the closed seam along the dorsal neural tube for maintenance of closure. We test this as well as alternative models, and evaluate downstream molecular and cellular pathways. PUBLIC HEALTH RELEVANCE: This Challenge Grant application addresses mechanisms of spina bifida using the mouse model system. Using a genetic approach, complemented with molecular and cellular assays, we dissect the developmental cause(s) of the fully penetrant spina bifida phenotype in mouse noggin mutants. Spina bifida is poorly understood in humans, yet affects affects approximately 2,000 of the approximately 4 million babies born each year in the US. Although usually not fatal in live-born infants if repaired surgically, lifetime complications typically occur, at an average cost of over $1 million per case.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (15) 转化科学，以及具体的挑战主题 15-NS-106：识别神经系统发育和功能的机制。该挑战赛征集了阐明神经系统形成原理的机制研究，以及对神经系统疾病中正常机制如何受到干扰的分析。脊柱裂是人类最常见的结构畸形之一；尽管死亡率和发病率很高，但脊柱裂的病因仍知之甚少。我们提出对 Noggin 突变小鼠腰椎裂的原因进行机制分析。与几乎所有其他具有神经管缺陷的小鼠品系相比，Noggin 的脊柱裂表型并不是由于背侧神经褶皱未能闭合成管而发生的。相反，闭合后一天左右，腰脊髓在中线的孤立区域中重新向背侧打开。这导致腰椎裂表型。这种突变体代表了一种尚未探索的脊柱裂机制的新型小鼠模型，与神经管无法闭合的模型相比，该模型可能与某些人类脊柱裂病例的发病机制更相关。我们使用组织特异性基因消融来确定个体组织对 Noggin 维持神经形成的需求。我们的初步数据表明，Noggin 促进神经管细胞与细胞粘附分子（如 N-钙粘蛋白）的粘附。我们的总体假设是，沿着背侧神经管的闭合缝需要 Noggin 来维持闭合。我们测试了这个模型以及替代模型，并评估下游分子和细胞途径。公共健康相关性：该挑战拨款申请使用小鼠模型系统解决脊柱裂的机制。使用遗传方法，辅以分子和细胞测定，我们剖析了小鼠头蛋白突变体中完全渗透性脊柱裂表型的发育原因。人们对脊柱裂知之甚少，但在美国每年出生的约 400 万婴儿中，约有 2,000 人受到脊柱裂的影响。虽然通过手术修复通常不会致命，但通常会出现终生并发症，每个病例的平均费用超过 100 万美元。