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: 8190226
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190226
• 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. PUBLIC HEALTH RELEVANCE: 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 mentored junior clinician-scientists prepared successful grant applications; the applicant participated fully in training medical students to perform research at an innovative medical school (the Cleveland Clinic Lerner College of Medicine (CCLCM); and the applicant mentored students from the high school level through post-doctoral fellowship with a high degree of success and productivity. He now seeks support to expand mentorship interactions with the CCLCM through membership on the Research Education Committee (REC), which reviews thesis project proposals, sets research policy and priorities for the CCLCM and develops tools to assist research mentors with their mission to graduate clinician- scientists from the CCLCM. He will incorporate a structured self-assessment plan, which will be used to enhance mentorship at the CCLCM. The applicant also proposes to participate in a new citywide clinical- translational research collaboration (newly funded by the National Institutes of Health) and will participate in choosing clinician scientists for research mentorship support, as well as in the mentoring process itself. Therefore, the applicant will integrate his extensive experience with mentorship into innovative and vigorous local/institutional programs. The research proposal focuses on a complex yet crucial question regarding the treatment of brain inflammation: how do we identify the safest and most important molecular targets, when we wish to block inflammatory white blood cells from migrating into the brain? The applicant has developed a new tissue-culture model which promises to accelerate research progress. Furthermore, research trainees working with this model will obtain experience doing bench work, and also in the design and interpretation of clinical-research experiments. Students and post-docs can participate in both the basic-science and clinical/translational elements of research using this novel system. Ultimately, they can use their own data to address which molecules represent logical targets for therapeutic blockade to ameliorate inflammatory neurological diseases.

描述（由申请人提供）：目前申请的持续资助计划是对前一个资助周期内富有成效的指导和研究进展的合理延伸，在此期间，有三名K08学员获得了可资助的R01优先分数；克利夫兰诊所勒纳医学院（CCLCM）的研究项目被纳入PI的指导活动；实验室博士后获得独立资助和/或教师职位；还有几位外部学员成功地竞争到了资金。我们现在寻求支持，通过研究教育委员会（REC）的成员扩大与CCLCM的指导互动，该委员会制定研究政策并开发工具，以协助研究导师完成从CCLCM毕业的临床科学家的使命。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的教师发展主任Christine Taylor博士会面，并讨论学生的反馈，这些反馈将用于加强CCLCM的研究指导。目前的申请也受益于NIH/ ncrr资助的凯斯西储大学医学院(CWRU-SOM)/克利夫兰诊所临床和转化科学合作（CTSC）的建立，其中包括一个临床科学家KL2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KL2临床科学家奖获得者的选拔和指导。总之，这些活动代表了申请人在克利夫兰诊所研究教育计划中的一个重要的新方向。该研究计划还利用了PI开发的一种新型血流增强的体外血脑屏障（BBB）模型，该模型将用于研究趋化因子受体在血流下如何被白细胞-内皮相互作用调节。这些实验包括趋化因子和脑微血管内皮细胞单层，并在专门为本研究开发的改良趋化室中进行分析。具体研究目的如下：目的1：明确趋化因子CXCL12如何选择性地向单核细胞发出信号，促进淋巴细胞的转运。目的2：建立腔内“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：确定腹腔“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个新系统参与基础和临床/转化研究，并使用他们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。