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Pro-inflammatory Mediator Crosstalk Induces COX-2 in Myofibroblasts via PKC/PKD

促炎介质串扰通过 PKC/PKD 诱导肌成纤维细胞中的 COX-2

基本信息

批准号：
8927614
负责人：
James Yoo
金额：
$ 15.34万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927614
关键词：
Address Advisory Committees Affect Agonist Animal Model Area Awareness Biological Process Bradykinin Cell Extracts Cell Line Cell physiology Cells Chronic Colorectal Cancer Colorectal Surgery Complex Data Development Development Plans Disease Environment Enzymes Event Family Foundations Functional disorder Funding Gastrointestinal tract structure Goals Grant Growth Factor Human Indium Inflammation Inflammation Mediators Inflammation Process Inflammatory Inflammatory disease of the intestine Intestinal Neoplasms Intestines Laboratories Lead Leadership Life Link Malignant Neoplasms Mediating Mentors Modeling Mus Myofibroblast Operative Surgical Procedures Pathogenesis Peptides Phosphorylation Physiological Play Population Positioning Attribute Process Production Protein Isoforms Protein Kinase Protein Kinase C Regulation Research Research Personnel Research Proposals Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Source Stimulus Stromal Cells TNF gene Time Tissues Training Ulcerative Colitis Up-Regulation Validation Well in self Work career career development citrate carrier colitis associated cancer colon carcinogenesis cyclooxygenase 2 cytokine design in vivo lectures meetings member mouse model novel novel therapeutics paracrine programs protein expression protein kinase D receptor response symposium teacher treatment strategy tumor tumor growth tumorigenesis willingness

项目摘要

DESCRIPTION (provided by applicant): Following the completion of my surgical training in General and Colorectal Surgery, I sought an academic position where I would have the best opportunity to achieve my long-term career goals of becoming an independently funded investigator, as well as an outstanding clinician and teacher. My life-long mentor, Dr. Jeffrey Matthews, guided my decisions in terms of choosing an academic environment where these goals would be strongly supported. I met with Dr. Enrique Rozengurt during the recruitment process, and his willingness to serve as my research mentor was a major factor in my decision to join the UCLA Department of Surgery in 2006. With the full support of my department, I have been working with Dr. Rozengurt since my arrival at UCLA. Under his guidance, I have laid the groundwork of a research proposal (this grant) that will serve as the foundation of an independent research program. With the additional guidance and expertise of Dr. Charalabos Pothoulakis, and the full support of my Department of Surgery under the leadership of Dr. Ronald Busuttil, I feel well positioned to succeed in my pursuit of a successful research career. Dr. Rozengurt, Dr. Pothoulakis, and Dr. Busuttil comprise my Advisory Committee, and with their help I have designed a Career Development Plan consisting of graduate level courses, weekly research seminars/lectures, formal laboratory meetings, and participation in national research conferences. My short-term goals are to gain expertise in areas of signal transduction and murine models of inflammation and colitis-associated cancer as I develop my own distinct focus of research. The association between chronic ulcerative colitis and the development of colorectal cancer is a well- established but incompletely understood phenomenon. Though the fundamental mechanism is not known, there has been a growing awareness of the contribution of the underlying intestinal stroma on inflammation-associated cancer. Colonic myofibroblasts are a subpopulation of cells located within the stroma of the GI tract that have been linked to both inflammation and tumorigenesis, and are a major source of cyclo-oxygenase 2 (COX-2), a critical enzyme also involved in these processes. However, the cell signaling pathways regulating COX-2 expression in myofibroblasts have not been well studied. Protein kinase D (PKD), the founding member of a new family of protein kinases that includes PKD2 and PKD3, has been implicated in important cellular functions but the expression, regulation and function of PKD in myofibroblasts, both in response to pro-inflammatory mediators and/or in the production of local regulators, has not been investigated. The central hypothesis of this proposal is that pro-inflammatory mediators activate a novel PKD phosphorylation cascade that plays a critical role in signal transduction pathways regulating colonic myofibroblast function. Using the human colonic myofibroblast cell line 18Co, our Preliminary Data demonstrate a synergistic upregulation of COX-2 protein expression following treatment with the inflammatory mediators TNF-( (TNF) and bradykinin (BK). This effect appears to be mediated by unique cross talk interactions between the distinct signaling pathways downstream of TNF and BK, leading to amplified PKD activation in direct association with a dramatic increase in COX-2 expression. The Specific Aims of this proposal are to 1) fully characterize the synergistic expression of COX-2 in response to pro-inflammatory mediators in colonic myofibroblasts, 2) identify mechanisms of signaling cross talk between pro-inflammatory mediators responsible for the synergy, 3) define the role of PKC/PKD signaling in the expression of COX-2 in myofibroblasts, and 4) substantiate the physiologic significance of these findings using a mouse model of colitis-associated cancer. Experimental results will also be confirmed using myofibroblast cells extracted from human colonic tissue taken at the time of surgery. Potential cross talk between TNF and BK in the synergistic enhancement of COX-2 expression in colonic myofibroblasts, mediated through PKD, may play an important role in colitis-associated cancer. PKD signaling may regulate key biological functions of myofibroblasts in the setting of inflammation.

描述（由申请人提供）：在完成我的普通和结直肠外科手术培训后，我寻求一个学术职位，在那里我将有最好的机会实现我的长期职业目标，成为一名独立资助的研究人员，以及一名优秀的临床医生和教师。我的终身导师杰弗里马修斯博士指导我选择一个能够有力支持这些目标的学术环境。在招聘过程中，我遇到了恩里克·罗森古特博士，他愿意担任我的研究导师是我决定在2006年加入加州大学洛杉矶分校外科系的主要因素。在我所在部门的全力支持下，自从我来到加州大学洛杉矶分校以来，我一直与Rozengurt博士合作。在他的指导下，我已经奠定了一个研究计划（这笔赠款）的基础，这将作为一个独立的研究计划的基础。有了Charalabos Pothoulakis博士的额外指导和专业知识，以及罗纳德布苏蒂尔博士领导下的我的外科部门的全力支持，我觉得自己有能力在追求成功的研究生涯中取得成功。Rozengurt博士、Pothoulakis博士和Busuttil博士组成了我的咨询委员会，在他们的帮助下，我设计了一个职业发展计划，包括研究生课程、每周的研究研讨会/讲座、正式的实验室会议和参加国家研究会议。我的短期目标是获得在信号转导和炎症和结肠炎相关癌症的小鼠模型领域的专业知识，因为我发展了自己独特的研究重点。慢性溃疡性结肠炎和结直肠癌的发展之间的关联是一个公认的但不完全理解的现象。虽然其基本机制尚不清楚，但人们越来越认识到肠道基质对炎症相关癌症的贡献。结肠肌成纤维细胞是位于胃肠道基质内的细胞亚群，其与炎症和肿瘤发生相关，并且是环加氧酶2（考克斯-2）的主要来源，环加氧酶2是也参与这些过程的关键酶。然而，调节肌成纤维细胞中考克斯-2表达的细胞信号通路尚未得到充分研究。蛋白激酶D（PKD）是包括PKD 2和PKD 3的蛋白激酶新家族的创始成员，其已经涉及重要的细胞功能，但是PKD在肌成纤维细胞中响应促炎介质和/或产生局部调节剂的表达、调节和功能尚未被研究。该提议的中心假设是促炎介质激活新型PKD磷酸化级联，其在调节结肠肌成纤维细胞功能的信号转导途径中起关键作用。使用人结肠肌成纤维细胞系18 Co，我们的初步数据表明，协同上调考克斯-2蛋白表达后，与炎症介质TNF-α（TNF）和缓激肽（BK）的治疗。这种效应似乎是由TNF和BK下游不同信号传导途径之间的独特串扰相互作用介导的，导致PKD活化放大，与考克斯-2表达的显著增加直接相关。该提议的具体目的是1）充分表征结肠肌成纤维细胞中响应促炎介质的考克斯-2的协同表达，2）鉴定负责协同作用的促炎介质之间的信号传导串扰的机制，3）定义PKC/PKD信号传导在肌成纤维细胞中考克斯-2表达中的作用，和4）使用结肠炎相关癌症的小鼠模型证实这些发现的生理学意义。还将使用从手术时采集的人结肠组织中提取的肌成纤维细胞确认实验结果。在PKD介导的结肠肌成纤维细胞考克斯-2表达的协同增强中，TNF和BK之间的潜在串扰可能在结肠炎相关癌症中发挥重要作用。PKD信号传导可以调节肌成纤维细胞在炎症环境中的关键生物学功能。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bradykinin stimulates protein kinase D-mediated colonic myofibroblast migration via cyclooxygenase-2 and heat shock protein 27.

DOI：
10.1016/j.jss.2016.10.014
发表时间：
2017-03
期刊：
The Journal of surgical research
影响因子：
0
作者：
Chu E;Saini S;Liu T;Yoo J
通讯作者：
Yoo J

Combined endoscopic and laparoscopic surgery may be an alternative to bowel resection for the management of colon polyps not removable by standard colonoscopy.

内窥镜和腹腔镜联合手术可能是肠切除术的替代方案，用于治疗标准结肠镜检查无法切除的结肠息肉。

DOI：
10.1007/s00464-012-2714-5
发表时间：
2013
期刊：
Surgical endoscopy
影响因子：
0
作者：
Lee,MinnaK;Chen,Formosa;Esrailian,Eric;Russell,MarciaMcGory;Sack,Jonathan;Lin,AnneY;Yoo,James
通讯作者：
Yoo,James

Colorectal emergencies: perforated diverticulitis (operative and nonoperative management).

结直肠急症：穿孔憩室炎（手术和非手术治疗）。