Analysis of Spatial & Temporal Dependence of Rhombic Lip Derivatives on Math1

空间分析

• 批准号: 7014632
• 负责人: STEPHEN M MARICICH
• 金额: $ 17.15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014632
• 关键词: phenotype; rhombencephalon

DESCRIPTION (provided by applicant): Disruptions of hindbrain development are implicated in multiple human disorders that cause significant morbidity and mortality such as Chiari malformations, sudden infant death syndrome and autism. The Math1 gene encodes a basic helix-loop-helix transcription factor whose function is necessary for the creation of multiple neuronal subtypes in the developing hindbrain, including those involved in breathing control. My proposal seeks to understand how Math1 contributes to normal hindbrain development in an effort to better understand derangements that cause serious neurodevelopmental human conditions. My goal is to determine how spatial and temporal cues specify the cellular fates of Math1-lineal cells derived from the rhombic lip. The Specific Aims of the project are to 1) disrupt Math1 function in a spatially restricted manner to define the sites of origin of various rhombic lip derivatives; 2) determine the time of origin of Math1-lineal cells; and 3) selectively eliminate Math1-dependent cell populations based on time of origin. I will use conditional knockout systems to test the hypothesis that disruption of Math1 in a spatial- or time-dependent manner causes deletion of specific subsets of neurons, resulting in different phenotypes depending on the cell groups that are affected. This strategy will allow me to construct a spatial and temporal fate map of the murine rhombic lip, pinpoint neurons essential for breathing control, and evaluate physiological and behavioral consequences resulting from loss of specific neuronal subsets in the hindbrain. My overall career goal is to become an independent physician/scientist who focuses on understanding congenital neurological abnormalities. I will spend the majority of my time running a basic research laboratory, but I will also see a select group of patients with brain malformations. My ultimate goal is to characterize and identify genes that are responsible for these abnormalities in the hopes of better understanding what causes them and how they may be effectively prevented or treated, if possible. Baylor College of Medicine provides the perfect environment for my success. My mentor, Dr. Huda Zoghbi, is an internationally known physician/scientist with a tremendous training record. Departmental support of my research career, interaction with a Scientific Advisory Committee, and formal coursework at Baylor and elsewhere will also help me to achieve my goals.

描述（由申请人提供）：后脑发育的破坏与多种人类疾病有关，这些疾病导致显著的发病率和死亡率，例如基亚里畸形、婴儿猝死综合征和自闭症。Math 1基因编码一种基本的螺旋-环-螺旋转录因子，其功能是在发育中的后脑中产生多种神经元亚型所必需的，包括参与呼吸控制的神经元亚型。我的建议旨在了解Math 1如何有助于正常的后脑发育，以更好地理解导致严重神经发育人类疾病的紊乱。我的目标是确定空间和时间线索如何指定来自菱形唇的Math 1线性细胞的细胞命运。该项目的具体目标是：1）以空间受限的方式破坏Math 1功能，以定义各种菱形唇衍生物的起源位点; 2）确定Math 1-线性细胞的起源时间; 3）基于起源时间选择性地消除Math 1依赖性细胞群。我将使用条件性敲除系统来测试以下假设：以空间或时间依赖性方式破坏Math 1会导致特定神经元子集的缺失，从而导致不同的表型，具体取决于受影响的细胞群。这种策略将使我能够构建小鼠菱形唇的空间和时间命运图，查明呼吸控制所必需的神经元，并评估后脑特定神经元子集丢失所导致的生理和行为后果。我的总体职业目标是成为一名独立的医生/科学家，专注于了解先天性神经异常。我将把大部分时间花在运行一个基础研究实验室上，但我也会看到一组脑畸形的病人。我的最终目标是描述和鉴定导致这些异常的基因，希望能更好地了解导致这些异常的原因，以及如何有效地预防或治疗这些异常。贝勒医学院为我的成功提供了完美的环境。我的导师Huda Zoghbi博士是一位国际知名的医生/科学家，拥有丰富的培训记录。部门对我的研究生涯的支持，与科学咨询委员会的互动，以及贝勒大学和其他地方的正式课程也将帮助我实现我的目标。