Neurotrophin- Chemokine Receptor Interactions Regulate Macrophage Activation

神经营养蛋白-趋化因子受体相互作用调节巨噬细胞激活

• 批准号: 8659199
• 负责人: Kimberly S. Williams
• 金额: $ 3.25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659199
• 关键词: Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Applications Grants; Area; Binding; Brain; CXCR4 gene; Calcium; Cell Survival; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Cessation of life; Chemokine (C-C Motif) Receptor 5; Color; Complex; Data; Development; Down-Regulation; Educational workshop; Ensure; Equilibrium; Event; Flow Cytometry; Foundations; Generations; Goals; Growth Factor; HIV; Human; Imaging Techniques; Immune; Inflammation; Inflammatory; Institution; Invaded; Investigation; Knowledge; Lead; Ligands; Location; Macrophage Activation; Measures; Microglia; Microscopy; NGFR Protein; Nerve Degeneration; Nerve Growth Factor Receptors; Nerve Growth Factors; Nervous System Physiology; Nervous System Trauma; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurons; Neuropathogenesis; Neurotoxins; Neurotrophic Tyrosine Kinase Receptor Type 1; Pathway Analysis; Pathway interactions; Phenotype; Phosphorylation; Play; Production; Public Speaking; Receptor Activation; Research; Research Ethics; Research Personnel; Research Project Grants; Role; Science; Signal Pathway; Signal Transduction; Source; Structure; Students; Techniques; Testing; Therapeutic; Training; Translational Research; Virus Diseases; Woman; Work; Writing; antiretroviral therapy; base; career development; chemokine receptor; knowledge base; macrophage; meetings; monocyte; nervous system disorder; neuroprotection; neurotoxic; neurotrophic factor; novel; novel therapeutics; prevent; programs; public health relevance; receptor; receptor expression; repaired; response; skills; success; symposium; transcriptional coactivator p75; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Applications Grants; Area; Binding; Brain; CXCR4 gene; Calcium; Cell Survival; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Cessation of life; Chemokine (C-C Motif) Receptor 5; Color; Complex; Data; Development; Down-Regulation; Educational workshop; Ensure; Equilibrium; Event; Flow Cytometry; Foundations; Generations; Goals; Growth Factor; HIV; Human; Imaging Techniques; Immune; Inflammation; Inflammatory; Institution; Invaded; Investigation; Knowledge; Lead; Ligands; Location; Macrophage Activation; Measures; Microglia; Microscopy; NGFR Protein; Nerve Degeneration; Nerve Growth Factor Receptors; Nerve Growth Factors; Nervous System Physiology; Nervous System Trauma; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurons; Neuropathogenesis; Neurotoxins; Neurotrophic Tyrosine Kinase Receptor Type 1; Pathway Analysis; Pathway interactions; Phenotype; Phosphorylation; Play; Production; Public Speaking; Receptor Activation; Research; Research Ethics; Research Personnel; Research Project Grants; Role; Science; Signal Pathway; Signal Transduction; Source; Structure; Students; Techniques; Testing; Therapeutic; Training; Translational Research; Virus Diseases; Woman; Work; Writing; antiretroviral therapy; base; career development; chemokine receptor; knowledge base; macrophage; meetings; monocyte; nervous system disorder; neuroprotection; neurotoxic; neurotrophic factor; novel; novel therapeutics; prevent; programs; public health relevance; receptor; receptor expression; repaired; response; skills; success; symposium; transcriptional coactivator p75

DESCRIPTION: Invading perivascular macrophages and microglia cell play a pivotal role in the neuropathogenesis of Human Immunodeficiency Virus (HIV) associated neurological disorders. As with many neurodegenerative diseases, the activation of macrophages and microglia cells in the central nervous system (CNS) is thought to contribute heavily to neuronal damage. However, these cells are very dynamic with a wide range of functions including neuroprotection and repair. It is becoming increasingly clear that strategies to modulate specific phenotypes of these cells have substantial therapeutic potential. The proposed studies will expand on ongoing research exploring how neurotrophin signaling through the p75 and TrkA receptors may suppress the neurotoxic activity of these cells with the intent of developing a novel neurotrophin-based anti- inflammatory therapy. Since little is known about the expression and functions of neurotrophin receptors on macrophages, characterization of the expression of the receptors and basic functional changes associated with neurotrophin stimulation is needed. The proposed studies will characterize the signaling pathways that contribute to the observed down regulation of inflammatory activity by these receptors. The potential receptor interactions and pathways are complex and advanced training in state of the art microscopy, imaging techniques, signaling pathway analysis, and flow cytometry techniques will greatly facilitate this effort. This training s available locally and from external focused workshops. Coursework, symposia and focused scientific meetings are included in the training plan to supplement gaps in current knowledge. In addition to attending focused sessions, this will provide opportunities for the candidate to actively present findings of the proposed work, while engaging and interacting with investigators from other institutions. Together the training will provide an in depth understanding of the dynamics of macrophage signaling in the context of various challenges and will provide new techniques to effectively measure changes in key signaling events associated with p75 and TrkA activation. The training plan also includes a strong focus on career development to ensure that the candidate will be prepared to transition from a student to a more mature investigator and eventually an independent translational researcher. Career development seminars and training sessions through the Science, Training and Diversity office covers research ethics, how to manage the many hurdles faced as a translational researcher and being a woman of color in the sciences, while also solidifying basic skills necessary for long-term success such as scientific writing, grant proposal development and public speaking. Overall, the plan is structured to support the long term goal of becoming a well rounded, creative and thought provoking neuroscientist capable of directing a program of research focused on the development of new therapies for neurodegenerative disorders.

描述：入侵血管周围巨噬细胞和小胶质细胞在人类免疫缺陷病毒（HIV）相关神经系统疾病的神经病发生中起关键作用。与许多神经退行性疾病一样，中枢神经系统（CNS）中巨噬细胞和小胶质细胞的激活被认为对神经元损伤有很大贡献。但是，这些细胞非常动态，具有广泛的功能，包括神经保护和修复。越来越清楚的是，调节这些细胞的特定表型具有巨大的治疗潜力。拟议的研究将扩大正在进行的研究，以探讨如何通过p75和TRKA受体进行神经营养蛋白信号传导如何抑制这些细胞的神经毒性活性，目的是开发一种新型的基于神经营养的抗炎症疗法。由于对神经营养蛋白受体在巨噬细胞上的表达和功能知之甚少，因此需要表征受体的表达以及与神经营养蛋白刺激相关的基本功能变化。拟议的研究将表征这些受体观察到的炎症活性调节的信号传导途径。潜在的受体相互作用和途径是在艺术显微镜，成像技术，信号通路分析和流式细胞仪技术中的复杂和先进的训练，将极大地促进这一工作。该培训在本地和外部专注的研讨会上可用。培训计划中包括课程工作，研讨会和专注的科学会议，以补充当前知识的差距。除了参加专注的会议之外，这还将为候选人提供机会积极地介绍拟议工作的发现，同时与其他机构的调查人员进行交流和互动。在各种挑战的背景下，训练将共同对巨噬细胞信号传导的动态有深入的了解，并将提供新技术，以有效地衡量与P75和TRKA激活相关的关键信号事件的变化。培训计划还包括对职业发展的重点，以确保候选人将准备从学生过渡到更成熟的研究者，并最终是独立的转化研究员。通过科学，培训和多样性办公室通过科学，培训和多样性办公室的职业发展研讨会和培训课程涵盖了研究伦理，如何管理作为转化研究人员面临的许多障碍，并成为科学上有色女性的女性，同时还巩固了长期成功的基本技能，例如科学写作，授予提案，赠款提案发展和公开演讲。总体而言，该计划旨在支持长期目标，即成为一个圆形，创造性和令人发指的神经科学家，能够指导一项研究计划，重点是开发神经退行性疾病的新疗法。