A genetically tractable model of tissue damage-induced nociceptive sensitization

组织损伤引起的伤害性敏化的遗传易处理模型

• 批准号: 7859856
• 负责人: MICHAEL J GALKO
• 金额: $ 28.97万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7859856
• 关键词: Affect; Afferent Neurons; Animals; Apical; Apoptosis; Apoptotic; Behavioral; Behavioral Assay; Biological; Biological Assay; Biological Models; Biological Process; Biology; Candidate Disease Gene; Caspase; Cell Death; Cells; Chronic Cancer Pain; Clinical; Collection; Complement; Defense Mechanisms; Development; Drosophila genus; Epidermis; Esthesia; Etiology; Event; Evolution; Gene Expression; Genes; Genetic; Genetic Models; Genetic Programming; Genetic Screening; Genome; Goals; Healed; Health; Homologous Gene; Human; Hyperalgesia; Injury; Kinetics; Larva; Ligands; Malignant Neoplasms; Mediator of activation protein; Molecular Genetics; Necrosis; Neurons; Nociception; Nociceptors; Operative Surgical Procedures; Organism; Pain; Process; Proteins; RNA Interference; Research Project Grants; Signal Transduction; Site; Stimulus; Syndrome; Testing; Tissue Model; Tissues; Transgenes; Translations; Trauma; Trauma recovery; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; UV induced; Up-Regulation; Vertebrates; Withdrawal; allodynia; base; chronic pain; gene conservation; gene discovery; gene function; genetic analysis; healing; in vivo; intercellular communication; knock-down; mutant; neuron development; novel; public health relevance; rapid detection; research study; response; theories; tool; ultraviolet irradiation

DESCRIPTION (provided by applicant): Multicellular organisms have evolved mechanisms to protect damaged tissue while it heals. One mechanism is a form of sensory neuron plasticity called nociceptive sensitization. This sensitization can manifest as aversive withdrawal to previously non- noxious stimuli (allodynia). Despite its biological and clinical importance, the genes required for nociceptive sensitization remain obscure. This research project focuses on the molecular genetic control of nociceptive sensitization in a model genetic organism where gene discovery is greatly facilitated. Our guiding hypothesis is that there is a conserved molecular genetic machinery that initiates, regulates, executes, and terminates nociceptive sensitization. To test this hypothesis we have established a nociceptive sensitization assay using Drosophila larvae and demonstrated that development of thermal allodynia requires the Drosophila homolog of the tumor necrosis factor (TNF) receptor and seventeen other genes we identified in a genetic screen for sensitization mutants. For this screen we tested whether larvae expressing gene-specific inhibitory RNAi transgenes specifically in nociceptive sensory neurons could develop allodynia normally following UV irradiation of the barrier epidermis. Our long-term objective is to use our unique assays and genetic tools to identify the complement of genes required in nociceptive sensory neurons for development of allodynia and to determine the specific function of these genes during sensitization. Our shorter-term goals are enumerated in the following specific aims: 1. To test the hypothesis that physical tissue damage (wounding) induces allodynia through different signals and mediators than UV-induced tissue damage. 2. To test the hypotheses that TNF induction following UV irradiation is apoptosis-independent, transcriptional, and/or translational/post-translational. And, 3. To characterize and identify novel genes required for nociceptive sensitization by expanding our genetic screen. This project represents the first systematic study of nociceptive sensitization in a model genetic organism and has great potential for uncovering the genes that initiate, execute, and regulate this process. Given the conservation of genes required for most fundamental neuronal functions we expect that this project will inform our understanding of nociceptive sensitization in vertebrates and in pathophysiological states, such as cancer and chronic pain syndromes, where this form of sensory neuron plasticity is thought to be improperly activated or regulated. PUBLIC HEALTH RELEVANCE: This research project employs a model genetic organism, the fruit fly, to uncover the genetic control of nociceptive (pain) sensitization, a process of immediate relevance to human health. Nociceptive sensitization is critical for organisms to protect sites of tissue injury, such as those caused by trauma or surgery, while they heal. Given the conservation of genes required for most fundamental biological processes, including neuronal function, we expect that this project will inform our understanding of nociceptive sensitization in vertebrates and in pathophysiological states, such as cancer and a variety of chronic pain syndromes, where the sensitization response is thought to be improperly activated or regulated.

描述(申请人提供)：多细胞生物体已经进化出在损伤组织愈合时保护其组织的机制。一种机制是一种称为伤害性敏感化的感觉神经元可塑性。这种敏感化可以表现为对先前非伤害性刺激(痛觉异常)的厌恶撤退。尽管它在生物学和临床上具有重要意义，但伤害性敏感化所需的基因仍然不清楚。本研究项目致力于在一个极大地促进基因发现的模式遗传有机体中，对伤害性敏化的分子遗传控制进行研究。我们的指导性假设是，有一种保守的分子遗传机制，启动、调节、执行和终止伤害性敏感化。为了验证这一假设，我们用果蝇幼虫建立了伤害性敏化实验，并证明了热性超敏痛的发生需要果蝇肿瘤坏死因子(TNF)受体的同源基因和我们在敏化突变体的遗传筛选中发现的其他17个基因。在这个筛选中，我们测试了在伤害性感觉神经元中特异表达基因特异性抑制性RNAi转基因的幼虫在紫外线照射屏障表皮后是否会正常地出现痛觉异常。我们的长期目标是使用我们独特的分析和遗传工具来确定伤害性感觉神经元中发生痛觉异常所需的基因互补，并确定这些基因在致敏过程中的特定功能。我们的短期目标列举在以下具体目标中：1.检验物理组织损伤(创伤)通过与紫外线诱导的组织损伤不同的信号和介质引起痛觉过敏的假说。2.验证紫外线照射后的肿瘤坏死因子诱导是非凋亡的、转录的和/或翻译/翻译后的假设。以及，3.通过扩大我们的基因筛选来表征和鉴定伤害性敏化所需的新基因。该项目代表了在模式遗传有机体中对伤害性敏感性的第一次系统研究，并在揭示启动、执行和调节这一过程的基因方面具有巨大的潜力。考虑到大多数基本神经功能所需的基因的保守性，我们预计这个项目将有助于我们理解脊椎动物以及癌症和慢性疼痛综合征等病理生理状态下的伤害性敏感化，在这些状态下，这种形式的感觉神经元可塑性被认为被不适当地激活或调节。 公共卫生相关性：这项研究项目使用了一种模式遗传有机体--果蝇，以揭示伤害(疼痛)敏化的基因控制，这是一个与人类健康直接相关的过程。伤害性敏感化对于生物在愈合过程中保护组织损伤部位至关重要，例如那些由创伤或手术造成的部位。考虑到大多数基本生物过程所需的基因的保守性，包括神经功能，我们预计这个项目将有助于我们理解脊椎动物和病理生理状态下的伤害性敏化，如癌症和各种慢性疼痛综合征，在这些敏化反应被认为被不适当地激活或调节。