Molecular Basis of Sensory Transduction in C. elegans

线虫感觉转导的分子基础

基本信息

批准号：
9295065
负责人：
Miriam B Goodman
金额：
$ 31.27万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9295065
关键词：
Address Affect Afferent Neurons Age Anabolism Animal Model Animals Apoptosis Arachidonic Acids Basic Science Biomedical Engineering Biophysics Bladder Caenorhabditis elegans Cell membrane Cells Chemicals Chimera organism Communication Complement Complex Cytoskeleton Diabetes Mellitus Disease Dissection Electrophysiology (science)Engineering Ensure Environment Event Fatty Acids Fatty acid glycerol esters Functional disorder Genetic Goals HIV Head and Neck Surgery Health Health Care Costs Impairment Ion Channel Ion Channel Protein Kidney Lead Lipids Mammals Measurement Measures Mechanics Mechanoreceptors Membrane Membrane Proteins Microtubules Modeling Molecular Mutation Nematoda Neurons Nociception Nociceptors Nonesterified Fatty Acids Organ Otolaryngology Palliative Care Perception Peripheral Nervous System Diseases Play Polyunsaturated Fatty Acids Process Property Proprioception Proteins RNA Interference Reporting Research Research Design Research Personnel Role Sensory Signal Transduction Skeleton Skin Sodium Spectrin Syndrome System TRP channel Techniques Testing Touch sensation Walking Withdrawal Work base biophysical analysis blood pressure regulation body position chemotherapy diabetic patient epithelial Na+ channel extracellular genetic analysis improved in vivo innovation mechanical load millisecond mutant neurotransmission normal aging novel optogenetics prevent programs public health relevance receptor response sensor sensory neuropathy somatosensory tool vibration

项目摘要

DESCRIPTION (provided by applicant): The gentlest breeze, the roughest sandpaper, and the sharpest pin are detected by our somatosensory system, which is composed of thousands of touch-sensitive mechanoreceptor neurons embedded in the skin. It is widely understood that physical force is transduced into neural signals through activation of specialized ion channels (called 'mechano-electrical transduction' or MeT channels), but understanding of the molecular and physical basis of this process remains rudimentary. All animals have the ability to sense touch and recent work has shown that nematode and mammalian somatosensory neurons have similar response dynamics (reviewed in Geffeney and Goodman, Neuron 74:609, 2012). This functional conservation is seen in neurons that rely on either DEG/ENaC or TRP channel proteins to form MeT channels, a finding which implies that response properties are conferred primarily by the cellular environment and not intrinsic to the ion channel proteins. The long-term goal of the proposed research program is to understand how the cell membrane and cytoskeleton regulate the delivery of physical force to MeT channels expressed in touch receptor neurons (TRNs) and discover the structural rearrangements associated with touch-evoked MeT channel gating. The general approach will be to combine in vivo recording of MeT channel gating in identified TRNs with genetic perturbations in C. elegans nematodes that 1) alter biosynthesis of polyunsaturated fatty acids and cell membrane function, 2) disrupt the microtubule and spectrin cytoskeleton and 3) disrupt selected domains in the MEC-4 proteins crucial to the formation of the sodium-selective native MeT channels,. This work will be paired with optogenetics studies designed to identify factors that affect MeT channels, but not downstream signaling events and with biophysical analysis of MeT channels expressed in heterologous cells. The proposed research combines expertise in sensory biophysics, in vivo electrical recording from identified C. elegans neurons, genetic analysis, to derive a profound understanding of the sense of touch. What is learned from these studies has the potential to improve understanding of touch sensation and its dysfunction in disease, during chemotherapy and as a consequence of normal aging.

描述（由申请人提供）：我们的体感系统可以检测到最轻柔的微风、最粗糙的砂纸和最锋利的针，该系统由嵌入皮肤的数千个触敏机械感受器神经元组成。人们普遍认为，物理力是通过激活专门的离子通道（称为“机电转导”或 MeT 通道）而转化为神经信号的，但对该过程的分子和物理基础的理解仍然处于初级阶段。所有动物都具有感知触觉的能力，最近的研究表明线虫和哺乳动物体感神经元具有相似的反应动力学（Geffeney 和 Goodman 综述，Neuron 74:609, 2012）。这种功能保守性见于依赖 DEG/ENaC 或 TRP 通道蛋白形成 MeT 通道的神经元，这一发现意味着反应特性主要由细胞环境赋予，而不是离子通道蛋白固有的。拟议研究计划的长期目标是了解细胞膜和细胞骨架如何调节物理力向触摸受体神经元（TRN）中表达的 MeT 通道的传递，并发现与触摸诱发的 MeT 通道门控相关的结构重排。一般方法是将已识别的 TRN 中 MeT 通道门控的体内记录与秀丽隐杆线虫线虫中的遗传扰动相结合，1) 改变多不饱和脂肪酸的生物合成和细胞膜功能，2) 破坏微管和血影蛋白细胞骨架，3)破坏 MEC-4 蛋白中对钠选择性天然 MeT 通道形成至关重要的选定结构域。这项工作将与旨在识别影响 MeT 通道但不影响下游信号事件的因素的光遗传学研究以及异源细胞中表达的 MeT 通道的生物物理分析相结合。拟议的研究结合了感觉生物物理学、已识别的秀丽隐杆线虫神经元的体内电记录、遗传分析等方面的专业知识，以获得对触觉的深刻理解。从这些研究中学到的东西有可能提高对触觉及其在疾病、化疗期间和正常衰老过程中的功能障碍的理解。

项目成果

期刊论文数量（43）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Patch clamp recording of ion channels expressed in Xenopus oocytes.

膜片钳记录非洲爪蟾卵母细胞中表达的离子通道。

DOI：
10.3791/936
发表时间：
2008
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Brown,AustinL;Johnson,BrandonE;Goodman,MiriamB
通讯作者：
Goodman,MiriamB

PTRN-1, a microtubule minus end-binding CAMSAP homolog, promotes microtubule function in Caenorhabditis elegans neurons.

DOI：
10.7554/elife.01498
发表时间：
2014-02-25
期刊：
eLife
影响因子：
7.7
作者：
Richardson CE;Spilker KA;Cueva JG;Perrino J;Goodman MB;Shen K
通讯作者：
Shen K

Phospholipids that contain polyunsaturated fatty acids enhance neuronal cell mechanics and touch sensation.

DOI：
10.1016/j.celrep.2013.12.012
发表时间：
2014-01-16
期刊：
Cell reports
影响因子：
8.8
作者：
Vásquez V;Krieg M;Lockhead D;Goodman MB
通讯作者：
Goodman MB

DEG/ENaC but not TRP channels are the major mechanoelectrical transduction channels in a C. elegans nociceptor.

DOI：
10.1016/j.neuron.2011.06.038
发表时间：
2011-09-08
期刊：
Neuron
影响因子：
16.2
作者：
Geffeney SL;Cueva JG;Glauser DA;Doll JC;Lee TH;Montoya M;Karania S;Garakani AM;Pruitt BL;Goodman MB
通讯作者：
Goodman MB

The DEG/ENaC protein MEC-10 regulates the transduction channel complex in Caenorhabditis elegans touch receptor neurons.

DOI：
10.1523/jneurosci.4580-10.2011
发表时间：
2011-08-31
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Arnadóttir J;O'Hagan R;Chen Y;Goodman MB;Chalfie M
通讯作者：
Chalfie M