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Project 2: Ganter

项目2：甘特

基本信息

批准号：
8689116
负责人：
GEOFFREY GANTER
金额：
$ 18.71万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8689116
关键词：
Adult Affect Alleles Animals Area Aversive Stimulus Behavioral Binding Biological Assay Biological Models Cell Nucleus Cells Chemical Stimulation Chemicals Data Dopamine Drosophila genome Drosophila genus Drosophila melanogaster Drug Addiction Drug Targeting Drug abuse Ecdysone Elements Eligibility Determination Food Future Genes Genetic Techniques Genomics Heating Homologous Gene Hormonal Human Hypersensitivity Instruction Knowledge Larva Lead Learning Libraries Link Mammals Mechanics Mediating Membrane Memory Modality Mutate Mutation Nature Nervous system structure Neurons Nociception Nuclear Organism Orthologous Gene Pain Pain management Painless Pathway interactions Perception Phenotype Process RNA Interference Research Personnel Role Sensory Sex Characteristics Signal Transduction Sleep Steroids Stimulus Stress Study models System TRP channel Testing Therapeutic Variant Vertebrates Visual system structure Work chemical hypersensitivity design ecdysone receptor fly genome wide association study genome-wide human disease interest memory process mustard oil mutant neurogenetics non-genomic novel relating to nervous system research study response steroid hormone temperature sensitive mutant

项目摘要

The modulation of nociception by novel factors including the steroid hormone ecdysone in the fruit fly will be investigated. The fruit fly Drosophila melanogaster model system has produced a quantity of data relevant to higher functions of the human nervous system, including findings in memory processing, sleep, drug abuse and addiction. Exploration of the neurogenetic and hormonal mechanisms controlling nociception in flies will increase our understanding of pain in humans. Using a mutant allele of the ecdysoneless (ecd^) steroid availability gene, we have shown in preliminary studies that when ecdysone is depleted in adult flies, they become hypersensitive to noxious thermal and chemical stimulation. This suggests that steroid signaling has an antinociceptive role in the fly, as has been shown in mammals. This finding establishes the fruit fly as a valid model for the study of steroid modulation of nociception, with implications extending to higher organisms such as humans. We will now characterize the cellular and subcellular nature of ecdysone's role in nociception, and identify other novel genes that are connected to antinociception in the fly. Aim 1 will test for alterations in nociception in flies with manipulated ecdysone levels. A temperature sensitive mutant allele of ecdysoneless, along with other mutants, will be used to ask whether ecdysone levels affect perception of, and behavioral responses to, noxious thermal, chemical and mechanical stimuli. Aim 2 will examine the mode of nociceptive ecdysone signaling in ecdysone receptor mutants. Experiments are designed to test whether disruption of ecdysone signaling at the level of the nucleus or at the membrane affects nociception, thereby determining if the mechanism of nociceptive modulation is a genomic or membrane process. Aim 3 will test for steroid modulation of identified nociceptive neurons. The potential role of ecdysone in the activity of known TRP channel-expressing nociceptive neurons will be assessed by temporal- and cell-specific blockade of signaling using genetic techniques. A parallel electrophysiological approach will also be used to analyze the response of TRP channel-expressing nociceptive neurons to varying levels of the steroid ecdysone. Aim 4 will screen a genome-wide mutant library to identify novel genes connected to antinociception in the fly. We will use a simple food-choice assay to rapidly identify mutants that are hypersensitive to a noxious chemical stimulus (mustard oil). This work should point to potentially novel human therapeutic drug targets.

包括类固醇激素蜕皮激素在内的新因子对果蝇伤害感受的调节将被讨论