Hippocampal Extracellular Matrix Regulates Glia-Neuron Crosstalk after Injury

项目摘要 意义：慢性疼痛影响美国30%的成年人，并伴有多种共病。 精神疾病，包括情绪改变和认知障碍。尽管这个问题很严重， 临床医生经常依靠“试错法”来找到提供某种缓解措施的策略。这 主要是因为大多数疼痛治疗是基于临床观察而不是机械的 了解慢性疼痛。其中一个关键机制可以解释疼痛的慢性化， 它对经典治疗的抵抗是疼痛集中的概念，最初的感觉事件 创伤后的疼痛可逐渐改变中枢神经系统（CNS），导致疼痛放大和/或异常 没有外周致敏的疼痛。然而，这一领域的大多数研究都集中在细胞 机制，并忽略了这些细胞发挥功能的细胞外基质（ECM）。拟议研究 旨在描绘脑ECM成分在疼痛相关的细胞和结构可塑性中的作用，从而 扩展了我们对慢性疼痛对大脑影响的认识。 创新：拟议的研究本质上是多模式的，并结合了与动物行为相关的技术， 细胞生理学、生物化学、细胞培养、药理学和显微学。例如，ECM刚度将 通过使用结构（扫描电子显微镜和物理显微镜后的微结构分析）进行评估 硬度使用原子力显微镜）以及生化分析（免疫组织化学和蛋白质 量化）。类似地，将在体内（药理学）和体内（药理学）评价特定ECM组分的作用。 和体外（使用独特的脱细胞脑基质进行神经元培养）。完成后 建议的研究，开发的工具集可以是一个有用的资产，在研究海马体以外的大脑区域。 代表性不足的少数群体参与生物医学/行为科学： 美国国立卫生研究院的使命是培养和毕业于全国生物医学代表性不足的群体的学生 研究，目前的建议专门针对皇后学院，纽约市立大学的多元化学生团体。皇后区 学院拥有高水平的种族和社会经济多样性，Tajerian博士致力于指导 她的系里有很多本科生和研究生。她有丰富的指导经验， 麦吉尔在斯坦福大学工作，她目前的实验室成员包括来自不同背景的学生。 博士Tajerian也是MARC-U* 星星指导计划的一部分。最大限度地获得研究职业是 学术研究本科生培训计划。这是第一个专门针对 专注于指导代表性不足的少数民族学生走向研究生院和生物医学研究事业。 时间轴和发展目标：所述实验的拟议时间轴为3年。数据 除了获得的技术专长外，在本赠款期间收集的资金将有助于 在慢性疼痛中的脑细胞外基质改变领域获得R 01级资助。

PROJECT SUMMARY Significance: Chronic pain affects 30% of the adult population in the USA and presents with multiple co-morbid psychiatric disorders, including mood alterations and cognitive impairment. Despite the severity of this problem, clinicians often rely on a “trial and error” approach to find a strategy that provides some measure of relief. This is mainly because most pain treatments were implemented based on clinical observations rather than a mechanistic understanding of chronic pain. One of the pivotal mechanisms that could explain the chronification of pain as well as its resistance to classical treatment is the concept of pain centralization, where initial sensory events following trauma can gradually alter the central nervous system (CNS), resulting in amplified pain and/or aberrant pain that exists without peripheral sensitization. However, most of the research in this area focuses on cellular mechanisms and overlooks the extracellular matrix (ECM) in which these cells function. The proposed research aims to delineate the role of brain ECM components in pain-related cellular and structural plasticity, thereby expanding our knowledge of the effects of chronic pain on the brain. Innovation: The proposed study is multimodal in nature and incorporates techniques related to animal behavior, cell physiology, biochemistry, cell culture, pharmacology, and microscopy. For instance, ECM rigidity will be assessed by using structural (microarchitectural analysis following scanning electron microscopy and physical rigidity using atomic force microscopy) as well as biochemical analyses (immunohistochemistry and protein quantification). Similarly, the role of specific ECM components will be evaluated both in vivo (pharmacology) and in vitro (using a unique decellularized brain substrate for neuronal culture). Upon the completion of the proposed studies, the developed toolset can be a useful asset in studying brain areas outside the hippocampus. Participation of underrepresented minorities in the biomedical/behavioral sciences: Consistent with the NIH’s mission of training and graduating students from groups nationally underrepresented in biomedical research, the current proposal specifically targets the diverse student body of Queens College, CUNY. Queens College boasts high levels of ethnic and socioeconomic diversity and Dr. Tajerian is committed to mentoring the many undergraduate and graduate students in her department. She has extensive mentorship experience both at McGill at Stanford universities, and her current laboratory members include students from diverse backgrounds. Dr. Tajerian is also part of the MARC-U*STAR mentoring program. Maximizing Access to Research Careers is an Undergraduate Student Training program in Academic Research. It is the first NIH program specifically focused on directing under-represented minority students toward graduate school and biomedical research careers. Timeline and developmental objectives: The proposed timeline for the outlined experiments is 3 years. Data collected for the duration of this grant, in addition to the acquired technical expertise, will be instrumental in the acquisition of R01 level funding in the field of brain extracellular matrix alterations in chronic pain.