Therapeutic Monitoring and Targeting of Neutrophil Activation in Pediatric IBD

儿童 IBD 中性粒细胞激活的治疗监测和靶向

• 批准号: 9047272
• 负责人: Phillip P Minar
• 金额: $ 17.55万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-06 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047272
• 关键词: Abdomen; Affect; Alternative Therapies; Anti-Tumor Necrosis Factor Therapy; Award; Biological Markers; Biometry; Child; Child health care; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Colonoscopy; Crohn' s disease; Development; Digestive System Disorders; Disease; Disease remission; Doctor of Philosophy; Early treatment; Endoscopy; Enrollment; Environment; Epithelial; Exposure to; Family; Fostering; Funding; Funding Opportunities; Gastroenterologist; Gastroenterology; Gene Expression; Gene Expression Profile; Genes; Goals; Healed; Health; Health Care Costs; Hepatology; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Intestinal Mucosa; Intestines; K-Series Research Career Programs; Knowledge; Lamina Propria; Lead; Learning Skill; Master of Science; Measures; Medical; Medical center; Mentors; Mentorship; Mission; Monitor; Monomeric GTP-Binding Proteins; Morbidity - disease rate; NADPH Oxidase; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Immunity; Neutrophil Activation; Newly Diagnosed; Operative Surgical Procedures; Outcome; Pathogenesis; Patient Care; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Pediatrics; Pharmacologic Substance; Physicians; Predictive Factor; Price; Production; Quality of life; Reactive Oxygen Species; Refractory; Relapse; Research; Research Personnel; Research Training; Resources; Role; Scientist; Secondary to; Services; Severities; Signal Transduction; Statistical Data Interpretation; Steroids; Surface; Symptoms; TNF gene; Testing; Therapeutic; Training; Translational Research; Ulcer; Ulcerative Colitis; United States; Up-Regulation; Work; base; care delivery; clinical care; clinical remission; cohort; comparative effectiveness; cytokine; discount; education research; effectiveness clinical trial; experience; gastrointestinal symptom; healing; health related quality of life; improved; in vitro testing; indexing; infancy; infliximab; inhibitor/antagonist; innovation; lifetime risk; meetings; minimally invasive; neutrophil; novel; novel marker; novel strategies; novel therapeutics; nutrition; pediatric department; pediatric patients; peripheral blood; preclinical study; prevent; professor; prospective; receptor; rectal; response; rho; rho GTP-Binding Proteins; skills; small molecule; specific biomarkers; success; targeted treatment; tool; transcriptome; treatment response; treatment strategy; trial design

 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.

 描述（由适用提供）：克罗恩病（CD）和溃疡性结肠炎（UC）目前在美国影响140万人，其中约有50,000名儿童。尽管药物治疗方面有很大改善，但绝大多数炎症性肠病（IBD）患者将需要继发于进行性肠道感染的腹部手术。此外，IBD相关的发病率对患者的生活质量产生了负面影响，并且与钢铁的医疗保健成本增加有关。我提出的职业发展奖的主要目标是获得有关生物统计学和先进免疫学的额外综合培训，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志物在纵向队列中，其目标是领导研究人员启发的临床试验，旨在提高IBD治疗的长期有效性。我是辛辛那提儿童医院医疗中心（CCHMC）的儿科，肝病学和营养学系的儿科教授和董事会认证的儿科胃肠病医生。 CCHMC的全球使命是通过完全综合的研究，教育和创新来改善儿童健康和改变护理的分娩。 CCHMC致力于开发一些年轻调查员，拥有几个机构资助机会，许多核心资源和培养协作研究环境。消化健康中心（DHC）是美国仅有的17个NIDDK资助的消化疾病研究核心中心之一，并以折扣价提供了对各种核心服务的访问。此外，临床和转化研究办公室（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了咨询支持。此外，CCHMC因其对小儿患者的卓越临床护理而受到国际认可，并为600名IBD儿童提供护理。医学博士Lee A. Denson是翻译和临床IBD研究的全国认可领导者，将担任我的主要导师。 Yi Zheng博士因其在Rho家族小型GTPase的细胞信号传导作用以及针对Rho GTPase信号轴的治疗剂的开发方面而受到国际认可，并将在此奖励期间提供冠军。我的近期目标是通过获得临床和转化研究，先天免疫，中性粒细胞功能分析，临床试验设计和进行纵向评估我们新型中性粒细胞生物标志物的纵向评估，以监测IBD儿童的新型中性粒细胞生物标志物，并进行纵向评估，从而获得了统计分析的其他专业知识。我们还将探讨活化中性粒细胞在肠道损伤中的致病作用，以进一步发展和 测试对当前治疗反应不佳的IBD患者的新型药物。我的长期目标是运用该奖项中学到的知识和技能，以获得独立的资金，作为一名实体主义者进行创新的临床和翻译研究。具体而言，在进行额外的培训之后，我将组建多中心协作o进行比较有效性临床试验，以提高小儿IBD中抗TNF治疗的短期和长期反应率。治疗至目标策略已成为一种新的方法，可以将治疗反应评估为优化的治疗方法，以防止肠道损伤并扭转当前手术的寿命风险 与严重的IBD相关。尽管靶向靶向策略仍处于起步阶段，但人们认识到，经常用疾病特定的生物标志物监测可能会通过在临床明显的症状之前提醒临床医生来改变结果，因为肠道炎症活动即使没有胃肠道症状也可能会持续存在。新型生物标志物的发展对于准确的生物标志物的成功至关重要 现有的IBD生物标志物反映了非特异性炎症负担，并且在肠道损伤的发病机理中并不直接隐含，而该疾病特异性临床指数严重低估了肠道炎症。这是对生物标志物的迫切需要，可以准确检测内窥镜感染/愈合，并在IBD发病机理中实施，因为它将为直接治疗提供IBD特定的靶标。在AIM 1中，我们将扩展以前的工作，并进一步定义多形核白细胞（PMN）CD64指数（CD64表面表达的标记）作为内窥镜严重程度和治疗反应的准确生物标志物。为了进行测试，我们将招募已转诊进行结肠镜检查的IBD患者，并确定PMN CD64指数在克罗恩病和溃疡性结肠炎中区分内窥镜严重程度评分（粘膜愈合，轻度，中度和严重）的能力。我们还将确定PMN CD64指数预测早期治疗反应的可能性并在纵向IBD患者中持续缓解的可能性启动英夫利昔单抗治疗。在AIM 2中，我们将进一步探讨IBD中PMN CD64表达对IBD肠上皮损伤的影响，通过评估来自外周血和肠道层次PMN的活性氧的产生。此外，我们将测试一种新型治疗化合物对PMN功能的影响，因为小分子靶标激活了PMN，并将作为对当前疗法反应较差的IBD患者的替代疗法。