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

空间分析

• 批准号: 7637551
• 负责人: STEPHEN M MARICICH
• 金额: $ 14.31万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 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/7637551
• 关键词: Advisory Committees; Affect; Autistic Disorder; BHLH Protein; Basic Science; Behavioral; Birth; Brain Stem; Breathing; Bromodeoxyuridine; Cell Nucleus; Cell division; Cells; Cerebellum; Code; Condition; Confidential Information; Cues; DNA Binding; Data; Dependence; Development; Disease; Disruption; Ear Nervous System; Embryo; Embryonic Development; Embryonic Nervous System; Environment; Epithelium; Failure; Funding; Gene Expression; Genes; Goals; Health; Human; Knock-out; Label; Laboratory Research; Language; Lip structure; Location; Maps; Mediating; Medicine; Mentors; Methods; Mission; Morbidity - disease rate; Mus; Neurologic; Neurons; Patients; Performance; Phenotype; Physicians; Physiological; Population; Public Health; Research; Research Design; Respiration; Role; Running; Scientist; Series; Site; Specific qualifier value; Sudden infant death syndrome; System; Techniques; Testing; Time; Training; base; behavior test; brain malformation; career; cell type; college; combinatorial; design; hindbrain; insight; malformation; mortality; precursor cell; prevent; research study; respiratory; success; transcription factor

State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. 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 Mathl gene encodes a basic helix-loop-helix transcription factor whose function is necessaryfor the creation of multiple neuronal subtypes in the developing hindbrain, including those involved in breathing control. My proposal seeks to understand how Mathl 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 MafM-lineal cells derived from the rhombic lip. The specific aims of the project are to 1) disrupt Math1function in a spatially- restricted manner to define the sites of origin of various rhombic lip derivatives; 2) determine the time of origin of Ma#77-lineal cells; and 3) selectively eliminate Mathl-dependent cell populations based on time of origin. I will use conditional knockout systemsto test the hypothesis that disruption of Mathl 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. PERFORMANCE

说明申请的广泛、长期目标和具体目标，并提及 该项目（即，与原子能机构的使命相关）。简要描述研究设计和实现这些目标的方法。描述 你将用来追求这些目标的基本原理和技术。 此外，用两三句话，用通俗的语言描述这项研究与公共卫生的相关性。如果申请得到资助， 这样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空间 提供了 后脑发育的中断与多种人类疾病有关， 发病率和死亡率，如基亚里畸形、婴儿猝死综合症和自闭症。数学 基因编码一个基本的螺旋-环-螺旋转录因子，其功能是产生 发育中的后脑中的多种神经元亚型，包括参与呼吸控制的神经元亚型。我 一项提案旨在了解Mathl如何促进正常的后脑发育，以更好地 了解导致严重的人类神经发育状况的紊乱。 我的目标是确定空间和时间线索如何指定MafM-线性细胞的细胞命运 源自菱形嘴唇。该项目的具体目标是：1）在空间上破坏Math 1功能- 限制的方式来确定各种菱形唇衍生物的起源地点; 2）确定时间 Ma#77-直系细胞的起源;和3）基于Mh 1-依赖性细胞群体的时间选择性地消除Mh 1-依赖性细胞群体。 起源我将使用条件性敲除系统来检验这一假设，即在一个空间或 时间依赖性方式导致特定神经元亚群的缺失，导致不同的表型 这取决于受影响的细胞群。这个策略将使我能够构建一个空间和 小鼠菱形唇的时间命运图，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 先天性神经异常我会把大部分时间花在基础研究上 实验室，但我也会看到一组大脑畸形的病人。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 了解是什么原因造成的，以及如何有效地预防或治疗。 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，拥有丰富的培训记录。部门支助 我的研究生涯，与科学咨询委员会的互动，以及贝勒大学的正式课程， 其他地方也将帮助我实现我的目标。 性能