Chemokine Regulation on Central Nervous System Inflammation in Multiple Sclerosis

描述(由申请人提供)：目前的K24继续支持申请是对上一个资助周期中生产性指导和研究进展的合乎逻辑的延伸，在此期间，三名K08指导对象获得了可资助的R01优先分数；克利夫兰临床勒纳医学院(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的资助和/或教师职位；几名外部指导对象成功竞争资金。我们现在寻求支持，通过研究教育委员会(REC)的成员资格来扩大与CCLCM的导师互动，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毕业临床医生-科学家。这项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Christine Taylor博士会面，并讨论学生的反馈，这些反馈将用于发展CCLCM的增强研究指导。目前的申请还受益于NIH/NCRR资助的凯斯西部储备大学医学院(CWRU-SOM)/克利夫兰临床与翻译科学合作(CTSC)的建立，其中包括临床医生-科学家KL2指导的博士后项目。申请者将加入CTSC的多学科咨询委员会(MAC)，参与KL2临床医生-科学家奖获得者的选择和指导。总之，这些活动代表了克利夫兰诊所研究教育计划中申请者的一个重要的新方向。该研究方案还利用了PI开发的一种新的流动增强型体外血脑屏障(BBB)模型，该模型将用于研究流动下白细胞-内皮相互作用如何调节趋化因子受体。这些实验包括趋化因子和脑微血管内皮细胞单层，分析是在专门为本研究开发的改装趋化室中进行的。具体的研究目标是：目标1：明确趋化因子CXCL12如何选择性地向单核细胞传递信号以促进淋巴细胞的迁移。目的2：探讨鲁米那类趋化因子对移行细胞趋化因子受体表达的调节作用。目的：研究白膜性“移行”趋化因子如何调节移行细胞趋化因子受体表达。学生和博士后都参与了使用这种新系统的研究的基本和临床/翻译元素，并使用他们自己的数据来确定哪些趋化因子受体代表神经疾病治疗干预的逻辑目标。 与公共卫生相关：目前的K24资助申请是上一个资助周期中生产性指导和研究进展的合乎逻辑的延伸，在上一个资助周期中，三名被指导的初级临床医生兼科学家准备了成功的资助申请；申请者全面参与了医学生在创新医学院(克利夫兰临床勒纳医学院(CCLCM))进行研究的培训；申请者通过博士后奖学金指导高中水平的学生，取得了很高的成功和生产力。他现在寻求支持，通过成为研究教育委员会(REC)的成员来扩大与CCLCM的导师互动，该委员会负责审查论文项目提案，为CCLCM制定研究政策和优先事项，并开发工具来帮助研究导师完成从CCLCM毕业的临床医生和科学家的任务。他将纳入一项结构化的自我评估计划，该计划将用于加强CCLCM的指导。申请者还建议参加一个新的全市临床-转化性研究合作(由美国国立卫生研究院新资助)，并将参与挑选临床科学家进行研究指导支持，以及指导过程本身。因此，申请者将把他在指导方面的丰富经验融入创新和充满活力的地方/机构项目。这项研究计划聚焦于一个关于治疗脑部炎症的复杂而关键的问题：当我们希望阻止炎性白细胞迁移到大脑中时，我们如何识别最安全和最重要的分子靶点？申请者开发了一种新的组织培养模式，有望加快研究进展。此外，使用这种模式工作的研究实习生将获得从事工作台工作的经验，以及临床研究实验的设计和解释方面的经验。学生和博士后可以使用这个新系统参与基础科学和临床/翻译方面的研究。最终，他们可以使用自己的数据来确定哪些分子代表了治疗阻断以改善炎症性神经疾病的逻辑靶点。

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.