PATTERNING THE DEVELOPING BRAIN

大脑发育的模式

• 批准号: 2682365
• 负责人: JEFFREY E MING
• 金额: $ 8.69万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-07 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2682365
• 关键词: animal genetic material tag; bone morphogenetic proteins; chick embryo; child (0-11); clinical research; congenital brain disorder; developmental genetics; developmental neurobiology; embryogenesis; gene induction /repression; gene mutation; human genetic material tag; human subject; neurogenesis; neurogenetics; nonmammalian vertebrate embryology; pathologic process; prosencephalon

Development of the brain is extraordinarily complex and requires the precise coordination of both cellular and molecular processes. The establishment of dorsal-ventral and rostral-caudal axes is an essential step in early brain formation. Disturbances in this process can result in Mental retardation and brain malformations. In fact, holoprosencephaly (HPE), a severe brain anomaly, can arise from abnormalities in genes regulating dorsal-ventral patterning. Haploinsufficiency for Sonic Hedgehog (Shh), a secreted factor which induces ventral identity of the brain, causes HPE in humans. In addition, overexpression of bone morphogenetic protein 5 (BMP5), a dorsal brain inducer, also results in HPE. These data indicate that HPE arises from aberrant dorsal-ventral specification. This proposal seeks to examine the mechanisms that determine dorsal- ventral axis formation in the, vertebrate forebrain and their relationship to the pathogenesis of human brain malformations. Since loss ot expression of Shh and ectopic expression of BMP5 both result in HPE, we hypothesize that mutations affecting other genes in these pathways will also disrupt normal patterning and lead to HPE. We will test this hypothesis in two ways. First, the mechanisms of BMP5 action in the forebrain will be examined by studying the function of BMP receptors (BMPRs) in the chick embryo, an established model of brain development. Constitutively active and dominant negative BMPR constructs will be expressed in the chick brain and the resulting morphologic, cellular, and genetic consequences will be analyzed. Second, since mutations in Shh are detected in only a fraction of HPE cases, mutation screening of several genes in the Shh and BMP pathways in individuals with HPE will be conducted. This proposal describes a five-year training program in which the applicant will acquire the skills and experience required of an independent physician scientist. The primary focus throughout the grant period will be laboratory benchwork, complemented by coursework, journal clubs, and limited clinical responsibilities relevant to the project. The expertise of the mentors will provide broad and in-depth training in two areas: an animal experimental model of development, and analysis of human genes. The proposed studies will enable the candidate to transition into an independent investigator capable of integrating mutation analysis, functional developmental studies, and clinical diagnosis in future studies of the molecular basis of development and human genetic diseases.

大脑的发育异常复杂，需要 细胞和分子过程的精确协调。 这 背腹轴和头尾轴的建立是至关重要的 早期大脑形成的一步。此过程中的干扰可能会导致 精神发育迟滞和脑畸形。 实际上， 前脑无裂畸形 (HPE) 是一种严重的大脑异常，可能由以下原因引起： 调节背腹模式的基因异常。 Sonic Hedgehog (Shh) 的单倍体不足，这是一种分泌因子， 诱导大脑腹侧特征，导致人类 HPE。 在 此外，骨形态发生蛋白 5 (BMP5) 的过度表达 背脑诱导剂，也会导致 HPE。 这些数据表明慧与 源于异常的背腹规格。 该提案旨在研究决定背侧的机制 脊椎动物前脑腹侧轴的形成及其 与人脑畸形发病机制的关系。 自从 Shh 表达缺失和 BMP5 异位表达都会导致 HPE，我们假设影响这些基因中其他基因的突变 途径也会破坏正常模式并导致 HPE。 我们将 用两种方式检验这个假设。 一、BMP5作用机制 将通过研究 BMP 的功能来检查前脑中的情况 鸡胚胎中的受体（BMPR）是一种已建立的大脑模型 发展。 组成性活跃和显性负性 BMPR 构建体将在小鸡大脑中表达，并产生结果 将分析形态、细胞和遗传后果。 其次，由于只有一小部分 HPE 中检测到了 Shh 突变 病例，Shh和BMP通路中多个基因的突变筛查 将在患有 HPE 的个人中进行。 该提案描述了一项为期五年的培训计划，其中 申请人将获得所需的技能和经验 独立医师科学家。 整个赠款的主要重点 期间将进行实验室实验，并辅以课程作业、期刊 俱乐部，以及与项目相关的有限临床责任。 导师的专业知识将提供广泛而深入的培训 两个领域：动物实验模型的开发和分析 人类基因。拟议的研究将使候选人能够 转变为能够整合的独立调查员 突变分析、功能发育研究和临床 未来发育和分子基础研究中的诊断 人类遗传疾病。