Neuronal membrane proteasome dependent regulation of PNS development and function

神经元膜蛋白酶体依赖性调节三七总皂苷的发育和功能

• 批准号: 10093710
• 负责人: Eric Villalon-Landeros
• 金额: $ 6.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2022-07-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093710
• 关键词: Address; Affect; Afferent Neurons; Antibodies; Axon; B-Lymphocytes; Biochemical; Biotinylation; Cell membrane; Cells; Coculture Techniques; Communication; Complex; Data; Defect; Development; Disease; Distal; Electrophysiology (science); Equilibrium; Extracellular Space; Foundations; Glycoproteins; Goals; Health; Health system; Horns; Human; Image; Immunoelectron Microscopy; Immunofluorescence Microscopy; In Vitro; Knock-out; Laboratories; Link; Lumbar spinal cord structure; Maintenance; Measurement; Measures; Mediating; Membrane; Membrane Proteins; Modality; Molecular; Mus; Myelin; Nature; Nervous system structure; Neuraxis; Neuroglia; Neurons; Outcome; Pathway interactions; Peptide Signal Sequences; Peptides; Peripheral Nervous System; Physiological; Plasmids; Play; Process; Proteasome Inhibition; Proteasome Inhibitor; Protein Biosynthesis; Proteins; Proteomics; Protocols documentation; Regulation; Research; Role; Schwann Cells; Sensory; Series; Signal Transduction; Spinal Cord; Spinal Ganglia; Surface; Systems Biology; Testing; Wild Type Mouse; Work; autocrine; base; design; experimental study; extracellular; feeding; improved; in vivo; inhibitor/antagonist; insight; multicatalytic endopeptidase complex; myelination; nervous system development; neuron development; neurotransmission; novel; overexpression; paracrine; protein degradation; protein purification; response; sciatic nerve

Development and function of the peripheral nervous system (PNS) requires a balance between protein synthesis and protein degradation, carried out in part by the proteasome complex. Our laboratory discovered a neuronal specific transmembrane-like proteasome complex with a new role in mediating neuronal signaling through direct peptide release into the extracellular space in the central nervous system. With our recent identification of the presence of this neuronal membrane proteasome (NMP) in the PNS our goal is to understand its role in mediating PNS development and signaling. Our central hypothesis is that NMP mediated signaling peptides have a pivotal role in PNS neuronal development and activity as well as in mediating axon-glia communication. Our rationale for this work is that the function of this recently identified NMP in the PNS is not understood and increasing the understanding of its function will reveal new modalities of neuronal signaling, which might be critical for optimal function of the PNS. Moreover, while a common appreciation for the impact of proteasomes signaling in the PNS in neuronal development and human health is understood the precise nature of the proteasome regulated pathways impacting PNS are not well delineated. Thus, our long-term goal is to understand the role of NMP in PNS biology in health and disease. Given the discovery of the NMP in the PNS was made recently in our laboratory several critical questions have emerged that make up the bases for the proposed experiments. Specifically: Aim1. To investigate the role of GPM6- like proteins in localizing membrane proteasomes in the PNS, to test our hypothesis that in the PNS NMP localizes to the neuronal membrane by associating with M6a/b glycoproteins; Aim 2. To investigate the requirement of PNS NMP in DRG neuron development, myelination, and activity, to test our hypothesis is that PNS NMP signaling is required for normal myelination and function of fully myelinated PNS neurons. Aim 3. To investigate the function of NMP peptides in axon-glia communication, to test our hypothesis that PNS axon-glia communication is, in part, mediated through NMP signaling peptides. The completion of the proposed aims will provide a foundation to continue the research that focuses on neuronal membrane proteasome signaling in the PNS.

周围神经系统（PNS）的发育和功能需要蛋白质合成和蛋白质降解之间的平衡，部分由蛋白酶体复合物进行。我们的实验室发现了一种神经元特异性跨膜样蛋白酶体复合物，其在通过直接将肽释放到中枢神经系统的细胞外空间中来介导神经元信号传导中具有新的作用。随着我们最近的鉴定，这种神经元膜蛋白酶体（NMP）在PNS中的存在，我们的目标是了解它在介导PNS的发展和信号传导中的作用。我们的中心假设是NMP介导的信号肽在PNS神经元的发育和活动以及介导轴突-胶质细胞通讯中具有关键作用。我们这项工作的基本原理是，这种最近确定的NMP在PNS中的功能尚不清楚，增加对其功能的了解将揭示新的神经元信号传导方式，这可能对PNS的最佳功能至关重要。此外，虽然对PNS中的蛋白酶体信号传导在神经元发育和人类健康中的影响的普遍认识是理解的，但影响PNS的蛋白酶体调节途径的精确性质没有很好地描述。因此，我们的长期目标是了解NMP在PNS生物学中对健康和疾病的作用。鉴于最近在我们的实验室中发现了PNS中的NMP，已经出现了几个关键问题，这些问题构成了拟议实验的基础。目标：1。研究GPM 6样蛋白在PNS中定位膜蛋白酶体中的作用，以检验我们的假设，即在PNS中NMP通过与M6 a/B糖蛋白缔合而定位于神经元膜;目的2.为了研究PNS NMP在DRG神经元发育、髓鞘形成和活性中的需求，为了验证我们的假设，即PNS NMP信号传导是完全髓鞘化的PNS神经元的正常髓鞘形成和功能所必需的。目标3。研究NMP肽在轴突-胶质细胞通讯中的作用，以验证我们的假设，即PNS轴突-胶质细胞通讯部分是通过NMP信号肽介导的。这些目标的实现将为进一步研究PNS中的神经元膜蛋白酶体信号通路奠定基础。