Therapeutic Monitoring and Targeting of Neutrophil Activation in Pediatric IBD

 描述(由申请人提供)：克罗恩病(CD)和溃疡性结肠炎(UC)目前在美国影响着140万人，包括大约50,000名儿童。尽管医学治疗有了很大的改进，但绝大多数炎症性肠病(IBD)患者将需要继发于进行性肠炎的腹部手术。此外，与IBD相关的发病率对患者的生活质量产生负面影响，并与医疗费用的急剧增加有关。我提议的职业发展奖的主要目标是获得额外的生物统计学和高级免疫学方面的全面培训，获得建立多中心合作所需的技能，并进一步检查我们的生物标记物的纵向队列，目的是领导研究人员发起的临床试验，旨在提高IBD治疗的长期疗效。我是辛辛那提儿童医院医学中心(CCHMC)儿科消化、肝病和营养科儿科的儿科学助理教授和委员会认证的儿科胃肠病专家。CCHMC的全球使命是通过完全整合的研究、教育和创新来改善儿童健康并改变护理提供方式。CCHMC致力于年轻研究人员的发展，拥有多个机构资助机会和众多核心资源，并促进合作研究环境。消化健康中心(DHC)是美国仅有的17个由NIDDK资助的消化疾病研究核心中心之一，以折扣价提供各种核心服务。此外，临床和翻译研究办公室(OCTR)和临床翻译研究中心(CTRC)在开发临床试验、研究监测、培训和统计分析方面提供咨询支持。此外，CCHMC以其对儿科患者的卓越临床护理而得到国际认可，并照顾&gt；600名IBD儿童。Lee A.Denson医学博士是全国公认的IBD翻译和临床研究领导者，他将担任我的主要导师。郑毅博士因其在Rho家族小GTP酶的细胞信号作用和针对Rho GTPase信号轴的治疗剂的开发方面的工作而受到国际认可，并将在此奖项期间提供共同指导。我的近期目标是通过获得临床和翻译研究、先天免疫、中性粒细胞功能分析、临床试验设计的理学硕士学位，获得更多统计分析方面的专业知识，并对我们用于监测和预测IBD儿童治疗反应的新型中性粒细胞生物标志物进行纵向评估。我们还将探讨激活的中性粒细胞在肠道损伤中的致病作用，以进一步发展和 为对当前治疗反应差的IBD患者测试新的药物。我的长期目标是应用在这个奖项中学到的知识和技能，作为一名进行创新临床和翻译研究的内科科学家，获得独立的资助。具体地说，在额外的培训之后，我将组成一个多中心合作，进行一项比较有效性的临床试验，以提高儿童IBD抗肿瘤坏死因子治疗的短期和长期应答率。靶向治疗策略已经成为一种频繁评估治疗反应的新方法，因为满足特定目标的优化医疗是预防肠道损伤和扭转目前手术的终身风险的关键。 与严重的IBD有关。尽管靶向治疗策略仍处于起步阶段，但人们认识到，频繁监测疾病特异性生物标志物可能会在临床症状出现之前提醒临床医生，从而改变预后，因为即使在没有胃肠道症状的情况下，肠道炎症活动也可能持续存在。新生物标记物的开发对这一治疗策略的成功至关重要，因为准确的生物标记物将使临床医生能够客观地评估正在进行的肠道炎症，并制定实现粘膜愈合的策略(内窥镜检查没有肠道溃疡)，因为这是唯一确定的预测因素。 以获得持续缓解。现有的IBD生物标志物反映的是非特异性炎症负担，与肠道损伤的发病机制没有直接关系，而疾病特异性临床指标严重低估了肠道炎症。因此，迫切需要能够准确检测内窥镜炎症/愈合并与IBD发病机制有关的生物标记物，因为它将为IBD的直接治疗提供特异性靶点。在目标1中，我们将扩展我们以前的工作，并进一步定义多形核白细胞(PMN)CD64指数(CD64表面表达的标志)作为内窥镜严重程度和治疗反应的准确生物标志物。为了测试这一点，我们将登记转诊为结肠镜检查的IBD患者，并确定PMN CD64指数区分克罗恩病和溃疡性结肠炎的内窥镜严重程度评分(粘膜愈合、轻度、中度和重度)的能力。我们还将确定PMN CD64指数预测开始英夫利昔单抗治疗的IBD患者的早期治疗反应和持续缓解的可能性。在目标2中，我们将通过评估外周血和肠固有层来源的PMN产生的活性氧物质，进一步探讨PMN CD64表达升高在IBD肠上皮损伤中的作用。此外，我们还将测试一种新的治疗化合物在体外对PMN功能的影响，作为激活PMN的小分子靶标，并将作为对现有治疗反应较差的IBD患者的替代治疗。

 DESCRIPTION (provided by applicant): Crohn's disease (CD) and ulcerative colitis (UC) currently affect 1.4 million people in the United States including approximately 50,000 children. Despite vast improvements in medical therapy, a large majority of inflammatory bowel disease (IBD) patients will require abdominal surgery secondary to progressive intestinal inflammation. Additionally, IBD related morbidity negatively impacts patient's quality of life and is associated with steep increases in health care costs. The primary goal of my proposed career development award is to acquire additional comprehensive training in biostatistics and advanced immunology, acquire the skills necessary to build multicenter collaborations, and further examine our biomarker in a longitudinal cohort with the goal to lead investigator-initiated clinica trials designed to improve the long-term efficacy of IBD therapy. I am an Assistant Professor of Pediatrics and a board-certified pediatric gastroenterologist in the Division of Gastroenterology, Hepatology and Nutrition in the Department of Pediatrics at Cincinnati Children's Hospital Medical Center (CCHMC). The global mission of CCHMC is to improve child health and transform care delivery through fully integrated research, education and innovation. CCHMC is dedicated to the development of young investigators with several institutional funding opportunities, numerous core resources and fosters a collaborative research environment. The Digestive Health Center (DHC) is one of only 17 NIDDK-funded Digestive Disease Research Core Centers in the United States and provides access to various cores services at a discounted price. In addition, the Office for Clinical and Translational Research (OCTR) and the Clinical Translation Research Center (CTRC) offers consultative support in developing clinical trials, study monitoring, training and statistical analysis. In addition, CCHMC is internationally recognized for its superior clinical care of pediatric patients and cares for >600 children with IBD. Lee A. Denson, MD is a nationally recognized leader in translational and clinical IBD research and will serve as my primary mentor. Yi Zheng, PhD is internationally recognized for his work on the cell signaling role of Rho family small GTPases and the development of therapeutic agents that target the Rho GTPase signaling axis and will provide co-mentorship during this award. My near-term goal is obtain additional expertise in statistical analysis by earning a Master of Science in Clinical and Translational Research, innate immunity, neutrophil function analysis, clinical trial design and conduct the longitudinal assessment of our novel neutrophil biomarker for monitoring and predicting treatment response in children with IBD. We will also explore the pathogenic role of activated neutrophils in gut injury to further develop and test novel pharmaceutical agents for IBD patients with poor responses to current therapy. My long-term goals are to apply the knowledge and skills learned during this award to obtain independent funding as a physician-scientist conducting innovative clinical and translational research. Specifically, following the additional training, I will form a multicenter collaboration o conduct a comparative effectiveness clinical trial to improve short and long term response rates to anti-TNF therapy in pediatric IBD. The treat-to-target strategy has emerged as a novel approach to frequently assess treatment response as optimized medical treatment that meets specific targets is the key to prevent gut injury and reverse the current lifetime risks of surgery associated with severe IBD. Although the treat-to-target strategy is in its infancy, it is recognizd that frequent monitoring with disease specific biomarkers may alter outcomes by alerting clinicians prior to clinically overt symptoms as intestinal inflammatory activity may persist even in the absence of gastrointestinal symptoms. The development of novel biomarkers is vital to the success of this treatment strategy as an accurate biomarker would allow clinicians to objectively assess ongoing intestinal inflammation and develop strategies to achieve mucosal healing (absence of intestinal ulcers by endoscopy) as it is the only established predictive factor for sustained remission. Existing IBD biomarkers reflect the non-specific inflammatory burden and are not directly implicated in the pathogenesis of gut injury while the disease-specific clinical indices grossly underestimate intestinal inflammation. Thus, there is a critical need for biomarker that accurately detects endoscopic inflammation/healing and is implicated in IBD pathogenesis as it would provide an IBD specific target to direct therapy. In Aim 1, we will extend our previous work and further define the polymorphonuclear leukocyte (PMN) CD64 index (a marker for CD64 surface expression) as an accurate biomarker of endoscopic severity and treatment response. To test this, we will enroll IBD patients who have been referred for colonoscopy and determine the capacity of the PMN CD64 index to discriminate between endoscopic severity scores (mucosal healing, mild, moderate and severe) in both Crohn's disease and ulcerative colitis. We will also determine the ability of the PMN CD64 index to predict the likelihood of early treatment response and sustained remission in a longitudinal cohort of IBD patients initiating infliximab therapy. In Aim 2, we will further explore the effect f elevated PMN CD64 expression on intestinal epithelial injury in IBD by evaluating the production of reactive oxygen species from peripheral blood and intestinal lamina propria derived PMN's. Additionally we will test the effect a novel therapeutic compound has on PMN functions in vitro as the small molecule targets activated PMN's and would function as an alternative therapy for IBD patients with a poor response to current therapies.