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

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：入侵的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发病机制中起关键作用。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是神经元损伤的主要原因。然而，这些细胞是非常动态的，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的策略具有实质性的治疗潜力。拟议的研究将扩展正在进行的研究，探索通过p75和TrkA受体的神经营养因子信号传导如何抑制这些细胞的神经毒性活性，目的是开发一种新的基于神经营养因子的抗炎疗法。由于对巨噬细胞中神经营养因子受体的表达和功能知之甚少，因此需要表征这些受体的表达以及与神经营养因子刺激相关的基本功能变化。所提出的研究将表征有助于这些受体观察到的炎症活性下调的信号通路。潜在的受体相互作用和途径是复杂的，先进的显微镜、成像技术、信号通路分析和流式细胞术技术的培训将极大地促进这一努力。该培训可在本地和外部重点讲习班进行。培训计划包括课程作业、专题讨论会和重点科学会议，以补充现有知识的空白。除了参加重点会议外，这将为候选人提供机会，在与其他机构的研究人员接触和互动的同时，积极展示拟议工作的发现。总之，培训将提供在各种挑战背景下巨噬细胞信号传导动力学的深入理解，并将提供有效测量与p75和TrkA激活相关的关键信号事件变化的新技术。培训计划还包括对职业发展的高度关注，以确保候选人准备好从学生过渡到更成熟的研究者，并最终成为独立的翻译研究者。通过科学、培训和多样性办公室举办的职业发展研讨会和培训课程涵盖了研究伦理、如何管理作为一名转化研究人员和作为一名有色人种女性在科学领域面临的许多障碍，同时也巩固了长期成功所需的基本技能，如科学写作、拨款提案制定和公开演讲。总的来说，该计划的结构是为了支持成为一个全面的、创造性的、发人深省的神经科学家的长期目标，能够指导一个专注于开发神经退行性疾病新疗法的研究项目。