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

结构性脑缺陷(SBDS)构成了一个巨大的健康问题。大约4%-6%的人类 人群受到影响神经系统结构的发育障碍的影响。大号 SBD病例的数量是或遗传来源的。尽管人类遗传学和基因组方面取得了重大进展 研究表明，大多数与SBD相关的基因仍然需要识别。还有一种迫切的需求 为动物模型研究大脑发育中的基因功能，确定脑血管疾病的分子发病机制 SBDS，并为其治疗开发治疗方法。值得注意的是，人类和小鼠的大脑 有许多解剖学和分子特征，表明控制中枢神经系统的遗传程序 发育在很大程度上是在两个物种之间保守的。鼠标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小鼠的正向和反向遗传学产生 有价值的动物模型用于研究控制大脑发育的遗传程序和定义 人类遗传性SBDS的分子发病机制。这一假设得到了我们的 初步数据，这表明我们可以通过正向和反向两种方式生成SBDS的小鼠模型 遗传学。因此，基于这些发现，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作为诱变剂的小鼠身上进行正向遗传学的专门知识，以产生患有 遗传性SBDS，定位克隆受影响的基因，并研究基因功能。另一个 计划项目拨款的参与者将测试我们识别的基因在多大程度上 与人类和斑马鱼的SBDS有关。在目标2中，我们将使用反向遗传学方法来 在人类或斑马鱼中产生携带与SBD相关的突变的小鼠系 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 导致SBD的一系列突变，并产生重要的小鼠模型来研究疾病机制。 相关性(请参阅说明)： 结构性脑缺陷(SBD)通常是由遗传引起的，也是最常见的脑部疾病之一 人类的结构性出生缺陷。这项提案寻求识别与SBDS相关的基因，并 开发用于研究疾病机制的小鼠模型。动物模型有很大的希望作为工具 发展治疗SBDS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.