Development of a mechanical nociceptive sensitization model in Drosophila

果蝇机械伤害感受敏化模型的开发

• 批准号: 8824247
• 负责人: MICHAEL J GALKO
• 金额: $ 24万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824247
• 关键词: Acute Pain; Afferent Neurons; Animals; Behavior; Behavioral Assay; Biological Assay; Biology; Burn injury; Clinical; Custom; Development; Diabetes Mellitus; Disease; Drosophila genus; Etiology; Event; Exposure to; Eye; Filament; Fostering; Future; Genes; Genetic; Genetic Models; Genetic Programming; Genetic Techniques; Genetic screening method; Goals; Healed; Histocompatibility Testing; Human; Hyperalgesia; Hypersensitivity; Injury; Investigation; Laboratories; Larva; Life; Malignant Neoplasms; Mechanical Stimulation; Mechanics; Modality; Modeling; Molecular; Molecular Genetics; Neurons; Nociception; Operative Surgical Procedures; Organism; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Phylogeny; Process; Radiation Injuries; Sensory; Signal Transduction; Site; Stimulus; Substance P; Surveys; Syndrome; System; TNF gene; Tachykinin; Testing; Tissues; UV induced; Ultraviolet Rays; Vertebrates; Withdrawal; Work; allodynia; base; chemotherapy; chronic pain; design; fly; gain of function; gene conservation; genetic analysis; healing; improved; intercellular communication; mechanical allodynia; nociceptive response; novel; public health relevance; response; smoothened signaling pathway; tissue trauma; tool

DESCRIPTION (provided by applicant): Pain sensitization is an adaptive response to tissue injury because it fosters behaviors that protect the site of injury while it heals. Sensitization cn occur across multiple sensory modalities such as thermal and mechanical and can manifest as responsiveness to previously non-noxious stimuli (allodynia) or exaggerated responsiveness to noxious stimuli (hyperalgesia). My laboratory has been modeling the thermal mode of nociceptive sensitization in Drosophila larvae since precise quantitative assays for this mode have been developed and refined. Clinically, however, mechanical hypersensitivity following tissue trauma, surgery, or in a variety of disease states that cause chronic pain (such as cancer and diabetes) is a more serious problem than the thermal mode. This is because patients encounter mechanical stimulation much more commonly in the course of daily life. Our goal in this R21 proposal is to develop the assays and tools and a sufficient basic genetic depth of understanding for the field to begin to dissect mechanical pain hypersensitivity in Drosophila. Our guiding hypothesis is that there is conserved molecular genetic machinery that initiates, regulates, executes, and terminates mechanical nociceptive sensitization. We have developed customized Von Frey filaments suitable for testing mechanical nociceptive responses in Drosophila larvae, have defined the precise noxious range for these animals, and have demonstrated the existence of mechanical allodynia and hyperalgesia following UV-induced tissue injury. Further, in a small-scale pilot screen we have identified a small number of genes required for mechanical nociception. Our project goals are enumerated in the following specific aims: 1. To test the hypothesis that particular types of tissue damage (physical wounding, burns, chemotherapy) are more potent at inducing mechanical nociceptive hypersensitivity. 2. To test the hypothesis that mechanical nociceptive hypersensitivity uses the same inducing signals as thermal nociceptive hypersensitivity. And, 3. To characterize novel genes required for mechanical nociceptive sensitization. This project represents the first systematic study of mechanical nociceptive sensitization in a model genetic organism and has great potential for uncovering the genes that initiate, execute, and regulate this process. It uses a template that we have already used successfully in our approach to studying thermal nociceptive sensitization. Given the conservation of genes required for most fundamental neuronal functions we expect that this project will inform our understanding of mechanical nociceptive sensitization in vertebrates and in pathophysiological states, such as cancer, diabetes, and chronic pain syndromes, where this form of sensory neuron plasticity is thought to be improperly activated or regulated.

描述（由申请人提供）：疼痛致敏是对组织损伤的适应性反应，因为它促进了在愈合时保护损伤部位的行为。敏化可以发生在多种感觉方式，如热和机械，可以表现为对先前非伤害性刺激的反应（异常性疼痛）或对伤害性刺激的过度反应（痛觉过敏）。我的实验室一直在模拟果蝇幼虫的伤害性致敏的热模式，因为这种模式的精确定量分析已经开发和完善。然而，在临床上，组织创伤、手术或导致慢性疼痛的各种疾病状态（如癌症和糖尿病）后的机械超敏反应是比热模式更严重的问题。这是因为患者在日常生活中更常遇到机械刺激。我们在R21提案中的目标是开发检测方法和工具，并对该领域有足够的基本遗传深度的理解，以便开始剖析果蝇的机械性疼痛超敏反应。我们的指导假设是，有保守的分子遗传机制，启动，调节，执行和终止机械伤害性敏化。我们已经开发出定制的Von Frey细丝适合于测试果蝇幼虫的机械伤害性反应，已经定义了这些动物的精确伤害范围，并证明了UV诱导的组织损伤后机械异常性疼痛和痛觉过敏的存在。此外，在一个小规模的试点筛选，我们已经确定了少量的基因所需的机械伤害。我们的项目目标列举在以下具体目标：1.检验特定类型的组织损伤（物理损伤、烧伤、化疗）更能诱导机械伤害性超敏反应的假设。2.为了验证机械伤害性超敏反应使用与热伤害性超敏反应相同的诱导信号的假设。三。鉴定机械伤害性致敏所需的新基因。该项目代表了在模型遗传生物中首次系统研究机械伤害性致敏，并具有很大的潜力来揭示启动，执行和调节这一过程的基因。它使用了一个模板，我们已经成功地使用我们的方法来研究热伤害性敏化。考虑到最基本的神经元功能所需的基因的保守性，我们期望该项目将告知我们对脊椎动物和病理生理状态（如癌症，糖尿病和慢性疼痛综合征）中的机械伤害性敏化的理解，其中这种形式的感觉神经元可塑性被认为是不适当的激活或调节。