Hippocampal Extracellular Matrix Regulates Glia-Neuron Crosstalk after Injury

海马细胞外基质在损伤后调节胶质细胞-神经元串扰

• 批准号: 10457472
• 负责人: Maral Tajerian
• 金额: $ 15.4万
• 依托单位: QUEENS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457472
• 关键词: Address; Adult; Affect; Anatomy; Animal Behavior; Area; Atomic Force Microscopy; Behavioral Sciences; Biochemical; Biochemistry; Biomedical Research; Biophysics; Brain; CCL7 gene; Cell Culture System; Cell Culture Techniques; Cell physiology; Cells; Clinical; Cognition; Data; Dendrites; Development; Environment; Event; Extracellular Matrix; Funding; Goals; Grant; Hippocampus (Brain); Immunohistochemistry; Impaired cognition; In Vitro; Injury; Knowledge; Laboratories; Limbic System; Measures; Memory; Memory impairment; Mental disorders; Mentors; Mentorship; Methods; Microdialysis; Microscopy; Mission; Modeling; Morphology; Mus; Nature; Neuraxis; Neuroglia; Neuromodulator; Neuronal Plasticity; Neurons; Nociception; Pain; Pain Clinics; Pain management; Pathway interactions; Patients; Peripheral; Pharmacology; Physiology; Population; Prevention; Proteins; Research; Resistance; Role; Scanning Electron Microscopy; Schools; Sensory; Severities; Signal Transduction; Structure; Students; Technical Expertise; Techniques; Tibial Fractures; TimeLine; Training; Training Programs; Trauma; Underrepresented Minority; United States National Institutes of Health; Universities; Western Blotting; affective disturbance; anxiety-like behavior; base; career; cell type; central pain; chronic pain; college; comorbidity; ethnic diversity; experience; experimental study; extracellular; graduate student; in vivo; innovation; limb fracture; member; minority student; multidisciplinary; multimodality; neuroinflammation; neuronal growth; new therapeutic target; novel strategies; pain chronification; pre-clinical; programs; socioeconomic diversity; therapeutic target; undergraduate student

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.

项目总结 意义：慢性疼痛影响了美国30%的成年人口，并呈现出多种并存症状 精神障碍，包括情绪变化和认知障碍。尽管这个问题很严重， 临床医生经常依靠“反复试验”的方法来寻找一种策略，以提供一定程度的缓解。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 对慢性疼痛的理解。可以解释疼痛慢性化的关键机制之一是 与其对经典治疗的抵抗力一样，疼痛集中的概念是最初的感觉事件 创伤后会逐渐改变中枢神经系统(CNS)，导致放大的疼痛和/或异常 没有外周敏感而存在的疼痛。然而，这一领域的研究大多集中在细胞上 而忽略了这些细胞发挥作用的细胞外基质(ECM)。拟议的研究 旨在阐明大脑细胞外基质成分在疼痛相关的细胞和结构可塑性中的作用，从而 扩大我们对慢性疼痛对大脑影响的知识。 创新：拟议的研究本质上是多模式的，并纳入了与动物行为相关的技术， 细胞生理学、生物化学、细胞培养、药理学和显微镜。例如，ECM刚性将为 使用扫描电子显微镜和物理分析后的结构(微体系结构分析)进行评估 刚性使用原子力显微镜)以及生化分析(免疫组织化学和蛋白质 量化)。同样，特定的细胞外基质成分的作用将在体内进行评估(药理学) 以及体外培养(使用一种独特的脱细胞大脑底物进行神经元培养)。在完成 在拟议的研究中，开发的工具包可以成为研究海马体以外的大脑区域的有用资产。 代表不足的少数群体参与生物医学/行为科学：符合 美国国立卫生研究院的使命是培养和毕业生物医学领域全国代表性不足群体的学生 根据研究，目前的提案专门针对纽约州立大学皇后学院的多样化学生群体。皇后区 大学拥有高度的种族和社会经济多样性，塔杰利安博士致力于指导 她系里有很多本科生和研究生。她拥有丰富的导师经验，在 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。 塔杰里安博士也是MARC-U*STAR指导计划的一部分。最大限度地获得研究职业机会是 本科生学术研究培训计划。这是美国国立卫生研究院第一个专门的项目 专注于引导代表不足的少数族裔学生走向研究生院和生物医学研究职业。 时间表和发展目标：所列实验的拟议时间表为3年。数据 在这笔赠款期间收集的资金，加上所获得的技术专门知识，将有助于 在慢性疼痛的脑细胞外基质改变领域获得R01水平的资金。

项目成果

Rapamycin Augmentation of Chronic Ketamine as a Novel Treatment for Complex Regional Pain Syndrome.

雷帕霉素增强慢性氯胺酮作为复杂区域疼痛综合征的新型治疗方法。

• DOI: 10.7759/cureus.43715
• 发表时间: 2023-08
• 期刊: Cureus
• 作者: Sharma A;Tajerian M;Berner J
• 通讯作者: Berner J

Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala.

• DOI: 10.1177/17448069221121307
• 发表时间: 2022-04
• 期刊: MOLECULAR PAIN
• 影响因子: 3.3
• 作者: Spinieli, Richard L.;Cazuza, Rafael Alves;Sales, Amanda Juliana;Gomes Carolino, Ruither Oliveira;Martinez, Diana;Anselmo-Franci, Janete;Tajerian, Maral;Leite-Panissi, Christie R. A.
• 通讯作者: Leite-Panissi, Christie R. A.

Garments and Footwear for Chronic Pain.

• DOI: 10.3389/fpain.2021.757240
• 发表时间: 2021
• 期刊: Frontiers in pain research (Lausanne, Switzerland)
• 作者: Tajerian M;Garcia J
• 通讯作者: Garcia J