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A new Drosophila model of astrocyte calcium signaling in chronic pain

慢性疼痛中星形胶质细胞钙信号传导的新果蝇模型

基本信息

批准号：
10196246
负责人：
Jeremy Thomas Smyth
金额：
$ 41.94万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196246
关键词：
Acute Address Adult Affect Amputation Animal Model Animal Testing Animals Astrocytes Calcium Signaling Cell membrane Cells Complex Cytoplasm Data Development Drosophila genus Etiology Event Exhibits Exploratory/Developmental Grant Frequencies Future Genetic Transcription Goals Homeostasis Injury Ions Leg Maintenance Measurement Mediating Modality Modeling Molecular Neuraxis Neuropathy Neurotransmitters Nociception Pain Pain Measurement Pain Research Pain management Physiology Process Quality of life Reporter Role Seminal Signal Transduction Synapses TRP channel Temperature Testing Therapeutic Thinness Time allodynia base central sensitization chronic neuropathic pain chronic pain design experimental study genetic approach in vivo innovation nerve injury non-opioid analgesic novel novel therapeutics pain behavior pain model painful neuropathy response sensory input therapeutic development tool

项目摘要

PROJECT SUMMARY Chronic neuropathic pain is a devastating condition that significantly impacts quality of life. Better understanding of how acute nerve injury transitions to chronic neuropathic pain is therefore a key initiative of pain research. Transition to neuropathic pain frequently involves central sensitization, where nociceptive networks in the central nervous system become hypersensitized to sensory inputs. During central sensitization astrocytes become highly reactive and release excitatory and synaptogenic factors that are required for nociceptive network sensitization. These astrocyte functions are regulated by Ca2+ signaling; however, the specific Ca2+ signaling mechanisms required in astrocytes for neuropathic pain are poorly understood. Astrocyte Ca2+ signaling involves somatic Ca2+ transients that traverse the entire cell body, and microdomain Ca2+ signals localized to thin astrocytic processes. Our functional understanding of these distinct astrocyte Ca2+ signals is limited by the complexity of mechanisms and channels that generate these signals in mammalian astrocytes. Our proposal will directly address this by taking advantage of recent seminal findings in Drosophila astrocytes demonstrating that somatic Ca2+ transients are mediated by the transient receptor potential (Trp) channel Waterwitch (Wtrw) and microdomain Ca2+ signals are mediated by TrpML channels. This provides us the means, for the first time, to genetically separate somatic and microdomain Ca2+ signals. We will combine this with a newly developed, adult Drosophila model of centrally mediated neuropathic pain. In Aim 1, we will determine how suppression of wtrw and trpml affects the development of neuropathic pain in adult Drosophila. In Aim 2, we will directly analyze somatic and microdomain Ca2+ signals in adult Drosophila astrocytes following acute injury. These experiments will allow us to clearly define the specific Ca2+ signaling mechanisms in astrocytes that drive neuropathic pain. This will represent an important breakthrough in our understanding of neuropathic pain etiology and may inform new pain therapeutic development.

项目摘要慢性神经性疼痛是一种严重影响生活质量的破坏性疾病。更好因此，了解急性神经损伤如何转变为慢性神经性疼痛是疼痛研究向神经性疼痛的转变通常涉及中枢敏感化，其中伤害性敏感化可导致神经性疼痛。中枢神经系统中的网络对感觉输入变得超敏。中枢致敏期间星形胶质细胞变得高度反应性，并释放兴奋性和突触发生因子，伤害性网络敏化。这些星形胶质细胞的功能是由Ca 2+信号调节的;然而，对于神经性疼痛的星形胶质细胞所需的特异性Ca 2+信号传导机制知之甚少。星形胶质细胞Ca 2+信号转导涉及贯穿整个细胞体的体细胞Ca 2+瞬变，以及微区 Ca 2+信号定位于薄的星形胶质细胞突起。我们对这些不同的星形胶质细胞的功能理解 Ca 2+信号受到产生这些信号的机制和通道的复杂性的限制，哺乳动物星形胶质细胞我们的建议将利用最近的开创性发现，果蝇星形胶质细胞证明体细胞钙瞬变是由瞬时受体介导的微区Ca ~（2+）信号是由TrpML通道介导的。这为我们提供了手段，第一次，在遗传上分离体细胞和微区Ca 2+信号。我们将联合收割机与新开发的成年果蝇中枢介导的神经性疼痛模型相结合。在目的1，我们将确定wtrw和trpml的抑制如何影响神经病理性疼痛的发展，成年果蝇目的2：直接分析果蝇体细胞和微区Ca 2+信号急性损伤后的星形胶质细胞。这些实验将使我们能够清楚地定义特定的Ca 2+信号传导星形胶质细胞中驱动神经性疼痛的机制。这将是我们的一个重要突破。了解神经病理性疼痛的病因，并可能告知新的疼痛治疗的发展。