Genetic analysis of nematode cell differentiation

线虫细胞分化的遗传分析

基本信息

批准号：
10552106
负责人：
MARTIN CHALFIE
金额：
$ 82.09万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-14 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552106
关键词：
Acetyltransferase Address Adhesions Affect Axonal Transport Binding Biological Process Caenorhabditis elegans Cell Differentiation process Cells Cholesterol Collection Complex Cryoelectron Microscopy Development Disease Extracellular Matrix Future Gap Junctions Generations Genes Genetic Goals Grant Health Heat-Shock Proteins 90 Human Individual Knowledge Maintenance Mammals Mechanics Molecular Chaperones Molecular Structure Mutation Nematoda Neurites Neuronal Differentiation Neurons Persons Phenotype Process Public Health Research Specific qualifier value Structure System Tissues Touch sensation Transcription Repressor Translating Translational Research Tubulin Visit Work alpha Tubulin axon guidance beta Tubulin experimental study gene discovery genetic analysis genetic approach insight mutant novel prevent protein degradation receptor tool transcription factor

项目摘要

We will continue our study of genes needed for neuronal differentiation and function using the six touch receptor neurons (TRNs) of the nematode Caenorhabditis elegans. Our previous research identified genes needed for the generation, specification, maintenance, and function of the TRNs. In the last grant period, we 1) identified a “double negative” type of neuronal specification, where an inhibitory transcription factor prevents the expression of a repressor transcription factor; 2) analyzed the effects of tubulin mutations on neuronal outgrowth; 3) used the suppression of mutations affecting a TRN-specific β-tubulin and a TRN-specific α-tubulin acetyltransferase as sensitized backgrounds to identify other genes needed for neuronal outgrowth, finding genes needed for protein degradation and gap-junction function; 4) discovered a novel balancing system needed for proper neurite outgrowth in which the protein degradation machinery is opposed by the HSP90 chaperone system; 5) demonstrated the usefulness of the Million Mutation Project (MMP) strains, a collection of completely sequence strains from the Waterston and Moerman labs, as a tool for gene discovery and identified many new touch mutants; 6) investigated neuronal ensheathment and discovered 14 new genes affecting it, including genes that are important for mechanosensory ECM, adhesion complexes, axon guidance, and axonal transport; and 7) discovered a synthetic ensheathment phenotype that we will exploit in the future. The general goal of the research going forward is to exploit these findings to understand how the differentiation of individual neurons is controlled and how mechanical inputs are sensed and modified. The most important experiments for the future are the elucidation of the molecular structure of the transduction complex using cryo-EM and the discovery and analysis of genes whose loss causes an increase in touch sensitivity, since these will be negative regulators of touch. We also intend to continue analyzing the new touch genes uncovered by our work with the MMMP strains, to revisit the analysis of an important cholesterol-binding component of the touch system (MEC-2), to exploit the discovery of a synthetic genetic relationship affecting TRN ensheathment to discover and characterize additional genes needed for this process. The health relatedness of our work comes from the discovery of new genes and new interactions among genes that are similar in humans and other mammals.

我们将继续研究神经元分化所需的基因和使用线虫Caenorhabdisis的六个触摸受体神经元（TRN）的功能秀丽隐杆线。我们以前的研究确定了这一代所需的基因， TRN的规范，维护和功能。在最后一个赠款期，我们1）确定了一种“双负”类型的神经元规范，其中抑制作用转录因子阻止了复制转录因子的表达； 2）分析了小节蛋白突变对神经元出生的影响； 3）使用了抑制影响TRN特异性β-微管蛋白和TRN特异性α-微管蛋白的突变乙酰基转移酶作为敏感背景，以识别神经元所需的其他基因生长，发现蛋白质降解和间隙结构功能所需的基因； 4）发现了一个新颖的平衡系统，用于适当的神经落生形象蛋白质降解机械与HSP90伴侣系统相反。 5）展示了百万突变项目（MMP）菌株的有用性，来自Waterston和Moerman Labs的完全序列应变，作为工具基因发现并确定了许多新的触摸突变体； 6）研究了神经元出发并发现了14个影响它的新基因，包括对于机械感应ECM，广告综合体，轴突指导和轴突很重要运输; 7）发现了我们将在未来。未来的研究的一般目标是将这些发现利用了解如何控制单个神经元的分化以及如何感知和修改机械输入。最重要的实验未来是使用翻译复合物分子结构的阐明冷冻EM以及对基因损失导致增加的基因的发现和分析触摸灵敏度，因为这些将是触摸的负调节器。我们也打算继续分析我们使用MMMP菌株的工作发现的新触摸基因，重新审视触摸系统中重要的胆固醇结合成分的分析（MEC-2），探索影响TRN的合成遗传关系的发现出现此过程所需的其他基因，以发现和表征。我们工作的健康相关性来自发现新基因和新基因人类和其他哺乳动物相似的基因之间的相互作用。