Chemokine Regulation on Central Nervous System Inflammation in Multiple Sclerosis

趋化因子对多发性硬化症中枢神经系统炎症的调节

• 批准号: 8703811
• 负责人: Richard M. Ransohoff
• 金额: $ 14.1万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-08 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703811
• 关键词: Address; Advisory Committees; Agonist; Applications Grants; B-Lymphocytes; Basic Science; Binding; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; CCL2 gene; CD8-Positive T-Lymphocytes; CX3CL1 gene; CXCL12 gene; CXCR4 gene; Cell Separation; Cells; Chemotaxis; Clinic; Clinical; Clinical Research; Clinical Sciences; Collaborations; Complement; Complex; Data; Development; Education; Elements; Encephalitis; Endothelial Cells; Endothelium; Engineering; Evaluation; Exhibits; Faculty; Feedback; Fellowship; Funding; Glycosaminoglycans; In Vitro; Inflammation; Inflammatory; Integrins; Laboratories; Leukocyte Rolling; Leukocytes; Ligands; Lymphocyte; Mediating; Medical Students; Medicine; Membrane Proteins; Mentors; Mentorship; Mission; Modeling; Molecular Conformation; Molecular Target; Multiple Sclerosis; National Center for Research Resources; Neuraxis; Patients; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Policy Research; Positioning Attribute; Postdoctoral Fellow; Process; Productivity; RANTES; Regulation; Research; Research Proposals; Scientist; Self Assessment; Signal Transduction; Solutions; Structure; Students; Surface; System; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic Intervention; Training; Translational Research; United States National Institutes of Health; Universities; Work; chemokine; chemokine receptor; college; cytokine; design; experience; healthy volunteer; high school; in vivo; innovation; medical schools; meetings; monocyte; monolayer; multidisciplinary; mutant; natalizumab; nervous system disorder; novel; programs; receptor; receptor expression; research study; response; success; therapeutic target; tissue culture; tool

DESCRIPTION (provided by applicant): The present application for continuing K24 support is a logical extension of productive mentorship and research progress during the prior cycle of funding, during which three K08 mentees achieved fundable R01 priority scores; the Cleveland Clinic Lerner College of Medicine (CCLCM) research program was integrated into the PI's mentorship activities; laboratory post-docs achieved independent funding and/or faculty positions; and several external mentees competed successfully for funding. We now seek support to expand mentorship interactions with the CCLCM through membership on the Research Education Committee (REC), which sets research policy and develops tools to assist research mentors with their mission to graduate clinician-scientists from the CCLCM. Integral to this activity is a structured evaluation process during which the PI will meet regularly with Dr. Christine Taylor, Director of Faculty Development for the Cleveland Clinic, and discuss student feedback, which will be used to develop enhance research mentoring at the CCLCM. The present application also benefits from establishment of the NIH/NCRR-funded Case Western Reserve University School of Medicine (CWRU-SOM)/Cleveland Clinic Clinical and Translational Science Collaborative (CTSC), which includes a clinician-scientist KL2 mentored post-doctoral program. The applicant will join the Multidisciplinary Advisory Committee (MAC) for the CTSC, participating in selection and mentorship of KL2 clinician-scientist awardees. Together, these activities represent a significant new direction for the applicant within the Cleveland Clinic's research education program. The research proposal also takes advantage of the PI's development of a novel flow-enhanced in-vitro blood-brain barrier (BBB) model, which will be used to examine how chemokine receptors are modulated by leukocyte-endothelial interactions under flow. These experiments incorporate chemokines and a brain microvascular endothelial cell monolayer, and assays are conducted in a modified chemotaxis chamber developed specifically for this research. Specific research aims are: Aim 1: To define how chemokine CXCL12 signals selectively to monocytes to promote transmigration of lymphocytes. Aim 2: To establish how luminal 'arrest' chemokines modulate chemokine receptor expression on transmigrated cells. Aim 3: To determine how abluminal 'transmigration' chemokines regulate chemokine receptor expression on transmigrated cells. Students and post-docs participate in both the basic and clinical/translational elements of research using this novel system and use their own data to address which chemokine receptors represent logical targets for therapeutic intervention in neurological disease.

描述（由申请人提供）：目前继续K24支持的申请是上一个资助周期中生产性指导和研究进展的逻辑延伸，在此期间，三名K 08学员获得了可资助的R 01优先分数;克利夫兰诊所勒纳医学院（CCLCM）研究计划被整合到PI的指导活动中;实验室博士后获得了独立资助和/或教职;几名外部学员成功竞争资金。 我们现在寻求支持，以扩大与CCLCM的导师互动，通过研究教育委员会（REC）的成员资格，该委员会制定研究政策，并开发工具，以帮助研究导师完成他们的使命，从CCLCM毕业的临床科学家。该活动的组成部分是一个结构化的评估过程，在此过程中，PI将定期与克利夫兰诊所教师发展主任克莉丝汀泰勒博士会面，并讨论学生反馈，这些反馈将用于加强CCLCM的研究指导。本申请还受益于NIH/NCRR资助的凯斯西储大学医学院（CWRU-SOM）/克利夫兰临床和转化科学合作组织（CTSC）的建立，其包括临床医生-科学家KL 2指导的博士后项目。申请人将加入CTSC的多学科咨询委员会（MAC），参与KL 2临床科学家获奖者的选拔和指导。总之，这些活动代表了克利夫兰诊所研究教育计划中申请人的一个重要的新方向。 该研究提案还利用了PI开发的一种新型流动增强的体外血脑屏障（BBB）模型，该模型将用于研究流动下白细胞-内皮细胞相互作用如何调节趋化因子受体。这些实验纳入趋化因子和脑微血管内皮细胞单层，并在专门为此研究开发的改良趋化性室中进行测定。具体的研究目的是：目的1：确定趋化因子CXCL 12如何选择性地向单核细胞发送信号以促进淋巴细胞的迁移。目的2：确定管腔“阻滞”趋化因子如何调节迁移细胞上趋化因子受体的表达。目的3：确定近腔“迁移”趋化因子如何调节迁移细胞上趋化因子受体的表达。 学生和博士后使用这种新系统参与研究的基础和临床/转化元素，并使用自己的数据来解决哪些趋化因子受体代表神经系统疾病治疗干预的逻辑靶点。

项目成果

Development, maintenance and disruption of the blood-brain barrier.

• DOI: 10.1038/nm.3407
• 发表时间: 2013-12
• 期刊: Nature medicine
• 影响因子: 82.9