Synthetic Clamping of Hyperalgesic Signaling

痛觉过敏信号的综合钳制

• 批准号: 10508966
• 负责人: Michael J Caterina
• 金额: $ 45.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10508966
• 关键词: Acylation; Afferent Neurons; Analgesics; Animal Model; Attenuated; Automobile Driving; Binding; Cell Line; Cell membrane; Cells; Clinical; Closure by clamp; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Engineering; Enzymes; Equilibrium; Event; Exhibits; Future; GTP-Binding Proteins; Genetic Transcription; Guanine Nucleotides; Immune; Ion Channel; Lead; Lipids; Measures; Mediating; Membrane; Monitor; Mus; NGFR Protein; Names; Nervous system structure; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; Nociception; Nociceptors; Output; Pain; Pain management; Pathologic; Pathway interactions; Peptide Hydrolases; Phosphoproteins; Phosphotransferases; Population; Process; Proteins; Receptor Protein-Tyrosine Kinases; Reflex action; Reporter; Research Personnel; Series; Signal Pathway; Signal Transduction; Signaling Protein; Spinal Ganglia; System; Translating; Work; base; cancer cell; chronic pain; experimental study; in vivo; in vivo Model; innovation; membrane activity; neurotransmitter release; novel therapeutics; pain chronification; pain sensation; pain sensitivity; protein activation; protein function; recruit; response; synthetic biology; therapy design; tool; tumor immunology

Pathological pain results in part from a dysequilibrium between pro- and anti-hyperalgesic signaling pathways in nociceptive neurons. Many available pain therapies are designed to inhibit specific pro-hyperalgesic signals or enhance specific anti-hypergesic signals. However, an alternative approach would be to proportionately redirect endogenous pathological pro- hyperalgesic signaling towards activation of anti-hyperalgesic pathways. Such an approach could clamp nociceptive function under evolving pathological conditions, and do so without compromising protective pain reflexes. In this proposal, we outline a strategy to redirect signaling from the pro-hyperalgesic TrkA receptor to achieve inhibition of pro-hyperalgesic cAMP and Ras/Rap driven signaling. We have developed a modular and customizable system, which we call Inducible Membrane Anchoring (IMA), that operates on the principle that many effector proteins function most efficiently when recruited to the plasma membrane, where their targets reside. We will first optimize this system in HEK293 cells, then move to cultured mouse dorsal root ganglion neurons, to determine if the cAMP and Ras/Rap pathways in those cells can be controllably modulated in this way. These studies will serve as proof-of-concept for future application of our hyperalgesic signal-shunting system in animal models in vivo and may lead to the development of novel therapies for pain. Furthermore, the modularity of our IMA system makes it adaptable to a wide range of input signals and output effectors. The tools and concepts that we develop may therefore have utility elsewhere in the nervous system and in other settings such as cancer and immunology.

病理性疼痛的部分原因是痛觉过敏和抗痛觉过敏之间的不平衡