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

描述（由申请人提供）：后脑发育的中断与多种人类疾病有关，这些疾病会导致严重的发病率和死亡率，如基亚里畸形、婴儿猝死综合征和自闭症。Math1基因编码一种基本的螺旋-环-螺旋转录因子，其功能对于发育中的后脑中多种神经元亚型的产生是必要的，包括那些与呼吸控制有关的亚型。我的提议旨在了解Math1如何促进正常的后脑发育，以便更好地理解导致严重的人类神经发育问题的紊乱。我的目标是确定空间和时间线索如何指定源自菱形唇的math1直系细胞的细胞命运。该项目的具体目标是：1)以空间受限的方式破坏Math1函数，以定义各种菱形唇导数的起源位置；2)确定math1 - linear细胞的起源时间；3)基于起源时间选择性地消除依赖math1的细胞群。我将使用条件敲除系统来测试假设，即以空间或时间依赖的方式破坏Math1会导致特定神经元子集的缺失，从而根据受影响的细胞组产生不同的表型。这一策略将使我能够构建小鼠菱形唇的时空命运图，精确定位呼吸控制所必需的神经元，并评估由于后脑中特定神经元亚群的丧失而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。我将花大部分时间管理一个基础研究实验室，但我也会看到一组精选的大脑畸形患者。我的最终目标是描述和识别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，以及如果可能的话，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。我的导师胡达·佐格比博士是一位国际知名的医生/科学家，有着丰富的训练记录。部门对我研究生涯的支持，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。

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.