Project 2. Mouse Models of Human Structural Brain Disorders: Forward and Reverse Genetics

结构性脑缺陷（SBD）是一个巨大的健康问题。大约4-6%的人类 人口受到影响神经系统结构的发育障碍的影响。大 SBD病例的数量或遗传起源。尽管人类遗传学和基因组取得了重大进展 研究表明，大多数与SBD相关的基因仍然需要鉴定。还迫切需要 用于动物模型研究发育中大脑的基因功能，以确定 SBD，并制定治疗方法。值得注意的是，人类和老鼠的大脑 共享许多解剖学和分子特征，这表明控制CNS的遗传程序 这两个物种的发育在很大程度上是保守的。老鼠也是一种领先的研究工具 用于基因研究。因此，我们假设，我们将通过正向和反向遗传学在小鼠中产生 有价值的动物模型，用于研究控制大脑发育的遗传程序， 人类SBD遗传形式的分子发病机制。这一假设得到了我们的支持。 初步的数据，这表明我们可以产生小鼠模型的SBD通过正向和反向 遗传学因此，根据这些研究结果，我们提出了两个具体目标。在目标1中，我们将利用 我们在使用ENU作为诱变剂的小鼠正向遗传学方面的专业知识， SBD的遗传形式，定位克隆受影响的基因，并研究基因功能。另 该计划项目赠款的参与者将测试我们识别的基因在多大程度上是 与人类和斑马鱼的SBD有关。在目标2中，我们将使用反向遗传学方法， 产生携带与人类或斑马鱼中的SBD相关的突变的小鼠品系， 由本计划项目建议书的其他参与者确定。我们预计，我们将确定一个广泛的 一系列导致SBD的突变，并产生重要的小鼠模型来研究疾病机制。 相关性（参见说明）： 结构性脑缺陷（SBD）通常是遗传性的，也是最常见的形式之一。 结构性先天缺陷该提案旨在确定与SBD相关的基因， 开发研究疾病机制的小鼠模型。动物模型作为工具有很大的希望， 开发治疗SBD的治疗方法。

Structural Brain Defects (SBDs) constitutes an immense health problem. Approximately 4-6% ofthe human population is affected by developmental disorders that affect the structure ofthe nervous system. A large number of SBD cases are or genetic origin. Despite major advances in human genetics and genome research, the majority of genes that are linked SBDs still need to be identified. There is also a pressing need for animal models to study gene function in the developing brain, to define the molecular pathogenesis of SBDs, and to develop therapeutic approaches for their treatment. Significantly, the brain of human and mice share many anatomical and molecular features, suggesting that the genetic program controlling CNS development is in large parts conserved between the two species. The mouse is also a leading research tool for genetic studies. We therefore hypothesize that we will generate by forward and reverse genetics in mice valuable animal models for studying the genetic program that controls brain development and for defining the molecular pathogenesis of inherited forms of SBDs in humans. This hypothesis is supported by our preliminary data, which show that we can generate mouse models for SBDs by forward and reverse genetics. Based on these findings, we therefore proposes two specific aims. In Aim 1, we will capitalize on our expertise in forward genetics in mice using ENU as a mutagen, to generate mouse lines afflicted with inherited forms of SBDs, to positionally clone the affected genes, and to study gene function. The other participants of the program project grants will test the extent to which the genes that we identify are associated with SBDs in humans and zebrafish. In Aim 2, we will use reverse genetics approaches to generate mouse lines carrying mutations associated with SBDs in humans or zebrafish that have been identified by the other participants of this program project proposal. We anticipate that we will identify a wide range of mutations that cause SBDs and generate important mouse models to study disease mechanisms. RELEVANCE (See instructions): Structural brain defects (SBDs) are frequently of genetic origin and one ofthe most common forms of structural birth defects in humans. This proposal seeks to identify genes that are linked to SBDs and to develop mouse models for studying disease mechanisms. The animal models hold great promise as tools for the development of therapeutic approaches towards the treatment of SBDs.