Investigating the function of localized BMP signaling at neuromuscular synapses

研究神经肌肉突触局部 BMP 信号传导的功能

• 批准号: 10292139
• 负责人: Mikolaj Sulkowski
• 金额: $ 37.81万
• 依托单位: SOUTHERN CONNECTICUT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292139
• 关键词: Acute; Address; Affect; Alzheimer' s Disease; Behavior Disorders; Binding; Biochemistry; Bone Morphogenetic Proteins; Brain; Cell Adhesion; Cell membrane; Cell physiology; Cells; Communication; Complex; Conscious; Development; Drosophila genus; Drosophila melanogaster; Electron Microscopy; Electrophysiology (science); Feedback; Functional disorder; Genes; Genetic; Genetic Models; Homeostasis; Human; Image; Immunoelectron Microscopy; Immunofluorescence Immunologic; Infrastructure; Kinetics; Knowledge; Learning; Link; Membrane; Methods; Microscopy; Minority-Serving Institution; Molecular; Molecular Biology; Movement; Nature; Nervous system structure; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Process; Property; Proteins; Regulation; Research Project Grants; Resolution; Role; Signal Transduction; Signaling Protein; Structure; Synapses; Synaptic Cleft; Synaptic Transmission; Testing; Thinking; Unconscious State; Work; addiction; autism spectrum disorder; experience; falls; in vivo; insight; intercellular communication; minority undergraduate; nervous system disorder; neural circuit; neural network; neuromuscular; neurotransmitter release; novel; postsynaptic; presynaptic; presynaptic neurons; protein complex; response; sensor; synaptic function; undergraduate student; voltage

Project Summary / Abstract Elucidating the molecular mechanisms that respond to membrane voltage changes at neuronal synapses and link these changes to the appropriate cellular responses is critical to physiology, as neural circuitry must maintain homeostasis while adapting to novel conditions, as well as in relation to neurological and neurodegenerative diseases, many of which ultimately result from defective synaptic transmission. Drosophila melanogaster has emerged as a powerful genetic model for dissecting such mechanisms. While significant progress has been made in identifying the structural components of synapses, as well as the molecules used by pre- and postsynaptic cells to communicate across the synaptic cleft, the mechanism by which these cellular processes integrate with transient changes in membrane voltage remain poorly understood. The current proposal will address this knowledge gap by focusing on how a noncanonical localized form bone morphogenetic protein (BMP) signaling at synapses serves as a sensor for membrane voltage, and the potential for this form of signaling to serve as an adapter between transient membrane voltage changes and more stable cellular alterations. We will test three central hypotheses: 1) that local BMP signaling responds to voltage changes at synapses; 2) that synaptic BMP signaling dynamically rises and falls in response to acute changes in membrane voltage; and 3) that synaptic BMP signaling complexes interact with a distinct suite of regulatory and effector molecules. These hypotheses will be tested by using a combination of in vivo genetics, gene editing, immunofluorescent microscopy, electron microscopy, molecular biology, biochemistry, and electrophysiology methods. The short-term impact of these studies will be novel insights into the molecular machinery linking membrane voltage changes with cellular and molecular alterations at Drosophila neuromuscular junction synapses. Ultimately, these studies may identify evolutionary conserved regulatory mechanisms with an important role in synaptic physiology in humans, and potentially contribute to our understanding of how disruptions in these cellular processes underlie the pathophysiology of neurological and neurodegenerative disease states.

项目总结/摘要 阐明神经元突触膜电压变化的分子机制， 将这些变化与适当的细胞反应联系起来对生理学至关重要，因为神经回路必须 保持体内平衡，同时适应新的条件，以及与神经和 神经退行性疾病，其中许多最终由突触传递缺陷引起。果蝇 黑腹果蝇已经成为剖析这种机制的一个强有力的遗传模型。虽然显著 在识别突触的结构成分以及所使用的分子方面已经取得了进展 通过突触前和突触后细胞跨越突触间隙进行交流，这些细胞 细胞过程与膜电压的瞬时变化结合仍然知之甚少。的 目前的建议将解决这个知识差距，重点是如何非规范的本地化形式骨 突触处的形态发生蛋白（BMP）信号传导充当膜电压的传感器，并且 潜在的这种形式的信号传导，以作为一个适配器之间的瞬态膜电压变化， 更稳定的细胞变化。我们将测试三个中心假设：1）局部BMP信号响应于 突触电压变化; 2）突触BMP信号动态上升和福尔斯响应急性 膜电压的变化;和3）突触BMP信号复合物与一套不同的 调节和效应分子。这些假设将通过使用体内遗传学， 基因编辑，免疫荧光显微镜，电子显微镜，分子生物学，生物化学，和 电生理学方法。这些研究的短期影响将是对分子生物学的新见解。 果蝇膜电压变化与细胞和分子改变的联系机制 神经肌肉接头突触。最终，这些研究可能会发现进化保守的调节基因， 在人类突触生理学中具有重要作用的机制，并可能有助于我们 了解这些细胞过程中的中断如何成为神经系统疾病的病理生理学基础， 神经退行性疾病状态。