Fyn activation in prion disease

朊病毒病中的 Fyn 激活

• 批准号: 9092646
• 负责人: Glenn C Telling
• 金额: $ 22.61万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9092646
• 关键词: Adult; Alzheimer' s Disease; Animals; Axon; Binding; Binding Proteins; Biochemical; Biological Neural Networks; Cell Death; Cell Proliferation; Cell Survival; Cells; Development; Disease; Disease Progression; Event; Human; Infection; Infection prevention; Interruption; Lead; Link; Measures; Mediating; Membrane Microdomains; Monitor; NCAM1 gene; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Odorant Receptors; Olfactory Epithelium; Pathogenesis; Pathology; Pathway interactions; Phenotype; Phosphorylation; Physiological; Play; Population; PrPC function; PrPSc Proteins; Prion Diseases; Prions; Proteins; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Staging; Structure; Synapses; System; Testing; Therapeutic Intervention; Toxic effect; neuron loss; neuronal survival; neurotoxicity; olfactory bulb; olfactory bulb glomeruli; olfactory sensory neurons; prevent; prion hypothesis; protein function; protein misfolding; protein protein interaction; public health relevance; synaptogenesis; therapeutic target

 DESCRIPTION (provided by applicant): Prion diseases are transmissible and fatal neurodegenerative diseases of animals and humans. The pathogenic mechanism of prion-induced neurotoxicity is not well defined, but it is proposed that either the loss of cellular prio protein (PrPC) function or gain of toxic function of PrPC and/or PrPSc plays a significant role in neurodegeneration. In this exploratory study we will examine the contribution of PrPC-mediated Fyn activation to the pathogenesis of prion disease. Fyn is an important regulator of synaptogenesis; under normal physiological conditions synapse formation can be dynamic, while during disease certain conditions can induce synaptic loss through the Fyn pathway. We propose that PrPC-mediated Fyn activation can cause neurotoxicity in prion neurodegeneration by either disruption of neuronal maturation and/or the loss of mature neurons. To test this hypothesis we will examine events upstream of PrPC signal transduction and monitor protein-protein interactions that regulate this pathway during prion neurodegeneration in olfactory sensory neurons (OSNs). This is an ideal system to investigate the role of PrPC in neurodegeneration because OSNs undergo continuous maturation in adults, but during prion infection there is reduced survival of OSNs. Analysis of proteins that bind to PrPC to initiate signal transduction, and the phosphorylation status of Fyn, can indicate the role of PrPC and Fyn activation in prion neurotoxicity. The second aim will be to determine whether prion infection blocks OSN maturation and to examine the status of PrPC-mediated Fyn activation during neuronal maturation and in differentiated OSNs. These studies will measure cell proliferation and survival of neurons in the olfactory epithelium to determine if neuronal maturation is inhibited or unimpeded. The third aim will investigate the effect of altered OSN axon targeting on neuron viability during prion neurodegeneration by measuring OSN synapses in glomeruli in the olfactory bulb and OSN cell bodies in the olfactory epithelium. This analysis will determine the role of OSN structural deficits on synapse formation and neuron survival during prion infection. Given the central role PrPC plays in both normal development and disease, in addition to its importance in PrPSc formation, understanding the role of PrPC in signal transduction pathways could reveal therapeutic targets to treat or prevent neurodegenerative diseases.

 描述（由申请人提供）：朊病毒疾病是动物和人类的传染性和致命性神经退行性疾病。朊病毒引起的神经毒性的致病机制尚未明确，但有人认为细胞朊蛋白（PrPC）功能的丧失或PrPC和/或PrPSc毒性功能的获得在神经退行性变中起重要作用。在这项探索性研究中，我们将研究PrPC介导的Fyn激活对朊病毒疾病发病机制的贡献。Fyn是突触发生的重要调节因子;在正常生理条件下，突触形成可以是动态的，而在疾病期间，某些条件可以通过Fyn途径诱导突触丢失。我们认为PrPC介导的Fyn激活可以通过破坏神经元成熟和/或成熟神经元的丧失引起朊病毒神经变性中的神经毒性。为了验证这一假设，我们将检查事件上游的PrPC信号转导和监测蛋白质-蛋白质相互作用，调节这一途径在朊病毒神经变性的嗅觉感觉神经元（OSN）。这是研究PrPC在神经变性中的作用的理想系统，因为OSN在成人中经历连续成熟，但在朊病毒感染期间，OSN的存活率降低。分析与PrPC结合以启动信号转导的蛋白质，以及Fyn的磷酸化状态，可以表明PrPC和Fyn活化在朊病毒神经毒性中的作用。第二个目的是确定朊病毒感染是否阻断OSN成熟，并检查神经元成熟过程中和分化的OSN中PrPC介导的Fyn激活状态。这些研究将测量嗅上皮中的细胞增殖和神经元的存活，以确定神经元成熟是否受到抑制或不受阻碍。第三个目标将通过测量嗅球中肾小球中的OSN突触和嗅上皮中的OSN细胞体来研究改变的OSN轴突靶向在朊病毒神经变性期间对神经元活力的影响。这项分析将确定在朊病毒感染过程中OSN结构缺陷对突触形成和神经元存活的作用。鉴于PrPC在正常发育和疾病中的核心作用，除了其在PrPSc形成中的重要性外，了解PrPC在信号转导途径中的作用可以揭示治疗或预防神经退行性疾病的治疗靶点。