MOLECULAR BIOLOGY OF OCULOMOTOR SYSTEM DEVELOPMENT

动眼系统发育的分子生物学

基本信息

批准号：
7825297
负责人：
Clifton W. Ragsdale
金额：
$ 29.51万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-05 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7825297
关键词：
Affect Axon BHLH Protein Biology Birds Brain Stem Candidate Disease Gene Cell Nucleus Cells Cephalic Chick Embryo Chickens Complex Computer Systems Development Defect Development Developmental Biology Disease Dissection Dopamine Electroporation Employee Strikes Gene Delivery Gene Expression Gene Transfer Techniques Generations Genes Goals Hereditary Disease Heterogeneity Homeobox Genes Homeodomain Proteins Human Genetics Midbrain structure Molecular Molecular Biology Motor Motor Neuron Disease Motor Neurons Mus Neurons Oculomotor nucleus Plants Play Population Primates Process Production Protein Isoforms RNA Interference Red nucleus structure Relative (related person)Research Research Personnel Resistance Role Site Specific qualifier value Spinal Cord Stem cells System Techniques Technology Testing Transcription factor genes Transgenic Organisms Ventricular Visceral Work base cell type hindbrain homeodomain innovation insight loss of function motor neuron development mutant neurogenesis novel therapeutics oculomotor orbit muscle overexpression programs prospective research study segregation transcription factor

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the molecular development of the nuclei and circuitry of the brainstem oculomotor control system. The focus of this project is on the regulatory mechanisms underlying oculomotor neuron production in the midbrain oculomotor complex (OMC) and the hindbrain trochlear nucleus (TrN). The proposed experiments will be carried out in chick embryos, which have the experimental advantage of site-directed transgenesis by electroporation and which share with other birds a highly organized OMC composed of discrete subnuclei with distinct extraocular muscle targets. The first set of experiments assesses the roles of homeodomain transcription factors in specifying oculomotor neuron identity and generating discrete OMC subnuclei. These experiments include a molecular dissection of the function of the CFEOM2 candidate gene PHOX2A. The second set of experiments investigates the molecular mechanisms that regulate the specification of midbrain progenitor cells to an oculomotor neuron fate, with a focus on the roles of NKX6 and basic helix-loop-helix transcription factors in these processes. The third set of experiments is based on our findings of pronounced transcription factor heterogeneity within the TrN and OMC subnuclei. We will investigate the anatomical correlate of this heterogeneity, focusing on the specific hypothesis that these molecular divisions identify motor neurons with distinct targets in the oculomotor plant. Study of the mechanisms that govern OMC and TrN development may provide insight into genetic diseases of the oculomotor system, most notably those such as CFEOM in which specific pools of oculomotor neurons are lost. More generally, understanding of the unique molecular specification of oculomotor cell types may suggest novel therapeutic strategies, including stem cell-based approaches, for the treatment of oculomotor disorders, and may give insight to the relative resistance of the oculomotor unit to some motor neuron diseases.

描述（由申请人提供）：这项研究的长期目标是了解脑干眼动力控制系统的细胞核和电路的分子发展。该项目的重点放在中脑眼动子络合物（OMC）和后脑干核核（TRN）中的动眼神经元产生的调节机制上。提出的实验将在雏鸡胚胎中进行，该实验具有通过电穿孔定向转基因的实验优势，并与其他鸟类共享一个由离散的subnuclei组成的高度有组织的OMC，该OMC由离散的亚核和具有独特的眼外肌肉靶标。第一组实验评估了同源域转录因子在指定眼动神经元同一性并产生离散OMC亚核中的作用。这些实验包括对CFEOM2候选基因PHOX2A功能的分子解剖。第二组实验研究了调节中脑祖细胞对眼球神经元命运的规范的分子机制，重点是NKX6和基本的螺旋 - 环螺旋转录因子在这些过程中的作用。第三组实验基于我们在TRN和OMC亚核中明显转录因子异质性的发现。我们将研究这种异质性的解剖学相关性，重点介绍了这些分子分裂鉴定动作植物中具有不同靶标的运动神经元的特定假设。研究控制OMC和TRN发育的机制可能会深入了解眼球系统的遗传疾病，最值得注意的是，诸如CFEOM丢失了特定的眼球神经元库的CFEOM。更普遍地，了解眼球细胞类型的独特分子规范可能表明新型治疗策略，包括基于干细胞的方法，用于治疗动眼疾病，并可能深入了解眼球单位对某些运动神经元疾病的相对抵抗力。