Chemokine Regulation on Central Nervous System Inflammation in Multiple Sclerosis

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）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金和/或教职;一些外部学员成功地竞争了资金。 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。 公共卫生相关性：目前继续K24支持的申请是上一个资助周期期间富有成效的指导和研究进展的合理延伸，在此期间，三名接受指导的初级临床医生-科学家准备了成功的赠款申请;申请人充分参与了培训医学生在创新医学院进行研究的工作（克利夫兰诊所勒纳医学院（CCLCM）;申请人通过博士后奖学金指导高中水平的学生，取得了很大的成功和生产力。他现在寻求支持，通过研究教育委员会（REC）的成员资格，扩大与CCLCM的导师互动，该委员会审查论文项目提案，为CCLCM制定研究政策和优先事项，并开发工具，以帮助研究导师完成他们的使命，从CCLCM毕业的临床医生-科学家。他将纳入一个结构化的自我评估计划，该计划将用于加强CCLCM的指导。申请人还提议参与一项新的全市范围的临床转化研究合作（由美国国立卫生研究院新资助），并将参与选择临床科学家进行研究指导支持，以及指导过程本身。因此，申请人将把他在导师方面的丰富经验融入到创新和充满活力的地方/机构项目中。这项研究计划关注的是一个复杂而关键的问题，即当我们希望阻止炎症性白色血细胞迁移到大脑中时，我们如何确定最安全和最重要的分子靶点？申请人开发了一种新的组织培养模型，有望加速研究进展。此外，使用该模型的研究学员将获得长凳工作以及临床研究实验的设计和解释的经验。学生和博士后可以使用这个新系统参与基础科学和临床/翻译研究。最终，他们可以使用自己的数据来解决哪些分子代表治疗阻断的逻辑靶点，以改善炎症性神经系统疾病。

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.