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（由申请人提供）：克罗恩病 (CD) 和溃疡性结肠炎 (UC) 目前影响美国 140 万人，其中包括约 50,000 名儿童。尽管药物治疗取得了巨大进步，但大多数炎症性肠病 (IBD) 患者因进行性肠道炎症而需要进行腹部手术。此外，IBD 相关发病率对患者的生活质量产生负面影响，并与医疗保健费用的急剧增加相关。我提出的职业发展奖的主要目标是获得生物统计学和高级免疫学方面的额外综合培训，获得建立多中心合作所需的技能，并在纵向队列中进一步检查我们的生物标志物，目的是领导研究者发起的临床试验，旨在提高 IBD 治疗的长期疗效。 我是辛辛那提儿童医院医疗中心 (CCHMC) 儿科胃肠病学、肝病学和营养科的儿科助理教授和委员会认证的儿科胃肠病学家。 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服务。 CCHMC 致力于培养年轻研究人员，拥有多个机构资助机会、众多核心资源，并营造协作研究环境。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，以折扣价提供各种核心服务。此外，临床和转化研究办公室 (OCTR) 和临床转化研究中心 (CTRC) 在开展临床试验、研究监测、培训和统计分析方面提供咨询支持。此外，CCHMC 因其对儿科患者的卓越临床护理而获得国际认可，并为超过 600 名 IBD 儿童提供护理。 Lee A. Denson 医学博士是全国公认的 IBD 转化和临床研究领导者，将担任我的主要导师。 Yi Cheng 博士因其在 Rho 家族小 GTPase 的细胞信号传导作用以及针对 Rho GTPase 信号传导轴的治疗药物开发方面的工作而获得国际认可，并将在该奖项期间提供共同指导。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、临床试验设计理学硕士学位来获得统计分析方面的额外专业知识，并对我们的新型中性粒细胞生物标志物进行纵向评估，以监测和预测 IBD 儿童的治疗反应。我们还将探讨活化的中性粒细胞在肠道损伤中的致病作用，以进一步开发和 为对当前治疗反应不佳的 IBD 患者测试新型药物。我的长期目标是运用在该奖项中学到的知识和技能，作为一名进行创新临床和转化研究的医师科学家获得独立资助。具体来说，在额外的培训之后，我将形成一个多中心合作，进行一项比较有效性的临床试验，以提高儿科 IBD 抗 TNF 治疗的短期和长期反应率。 靶向治疗策略已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当前手术终生风险的关键 与严重的 IBD 相关。尽管靶向治疗策略还处于起步阶段，但人们认识到，频繁监测疾病特异性生物标志物可能会在出现临床明显症状之前向临床医生发出警报，从而改变结果，因为即使没有胃肠道症状，肠道炎症活动也可能持续存在。新型生物标志物的开发对于这种治疗策略的成功至关重要，因为准确的生物标志物将使临床医生能够客观评估持续的肠道炎症并制定实现粘膜愈合（内窥镜检查无肠溃疡）的策略，因为它是唯一已确定的预测因素 以达到持续缓解。现有的 IBD 生物标志物反映了非特异性炎症负担，并不直接涉及肠道损伤的发病机制，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志物，因为它可以为指导治疗提供 IBD 特异性靶标。 在目标 1 中，我们将扩展我们之前的工作，并进一步定义多形核白细胞 (PMN) CD64 指数（CD64 表面表达的标记）作为内镜严重程度和治疗反应的准确生物标记。为了测试这一点，我们将招募已转诊进行结肠镜检查的 IBD 患者，并确定 PMN CD64 指数区分克罗恩病和溃疡性结肠炎内镜严重程度评分（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 患者纵向队列中早期治疗反应和持续缓解的可能性的能力。在目标 2 中，我们将通过评估外周血和肠固有层衍生的 PMN 产生的活性氧簇，进一步探讨 PMN CD64 表达升高对 IBD 肠上皮损伤的影响。此外，我们将在体外测试新型治疗化合物对中性粒细胞功能的影响，因为该小分子靶向激活的中性粒细胞，并将作为对当前疗法反应不佳的 IBD 患者的替代疗法。