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: 9243245
• 负责人: Phillip P Minar
• 金额: $ 18.99万
• 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/9243245
• 关键词: 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one; 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; Consultations; Crohn' s disease; Development; Digestive System Disorders; Disease; Disease remission; Doctor of Philosophy; Early treatment; Education; Endoscopy; Enrollment; Environment; Epithelial; Exposure to; Family; Fostering; Funding; Funding Opportunities; Gastroenterologist; Gastroenterology; Gene Expression; Gene Expression Profile; Genes; Goals; Health; Health Care Costs; Hepatology; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; International; Intestinal Mucosa; Intestines; K-Series Research Career Programs; Knowledge; Lamina Propria; Lead; Longitudinal cohort; Master of Science; Measures; Medical; Medical center; Mentors; Mentorship; Mission; Modernization; 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; Pathogenicity; Patient Care; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Pediatrics; Pharmacologic Substance; Physicians; Predictive Factor; Price; Production; Prospective cohort; 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; Subgroup; Surface; Symptoms; TNF gene; Testing; Therapeutic; Training; Translational Research; Ulcer; Ulcerative Colitis; United States; Up-Regulation; Work; base; care delivery; clinical care; clinical remission; clinical translation; cohort; comparative effectiveness; cytokine; discount; effectiveness clinical trial; experience; gastrointestinal symptom; healing; health related quality of life; improved; in vitro testing; indexing; infancy; infliximab; inhibitor/antagonist; innovation; lifetime risk; minimally invasive; neutrophil; novel; novel marker; novel strategies; novel therapeutics; nutrition; pediatric department; pediatric patients; peripheral blood; preclinical study; predictive of treatment response; prevent; professor; public health relevance; receptor; rectal; response; rho; rho GTP-Binding Proteins; skills; small molecule; specific biomarkers; success; targeted treatment; therapeutic development; 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，包括约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道炎症的腹部手术。此外，IBD相关的发病率对患者的生活质量产生负面影响，并与医疗保健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，目标是领导旨在提高IBD治疗长期疗效的临床试验。 我是辛辛那提儿童医院医学中心（CCHMC）儿科胃肠病学、肝病学和营养学部门的儿科助理教授和委员会认证的儿科胃肠病学家。CCHMC的全球使命是通过全面整合的研究，教育和创新来改善儿童健康并改变护理服务。CCHMC致力于发展年轻的研究人员，提供多个机构资助机会，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NIDDK资助的消化疾病研究核心中心之一，并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因其对儿科患者的上级临床护理而获得国际认可，并为超过600名IBD儿童提供护理。李·A Denson博士是国家公认的转化和临床IBD研究的领导者，并将担任我的主要导师。Yi Zheng博士因其在Rho家族小GTPases的细胞信号传导作用方面的工作以及靶向Rho GTPases信号传导轴的治疗药物的开发而获得国际认可，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转化研究，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，以进一步发展和 为对当前治疗反应差的IBD患者测试新的药物制剂。我的长期目标是应用在这个奖项学到的知识和技能，以获得独立的资金作为一个医生，科学家进行创新的临床和转化研究。具体来说，在额外的培训之后，我将组建一个多中心合作组织，进行一项比较有效性的临床试验，以提高儿科IBD患者对抗TNF治疗的短期和长期应答率。 达标治疗策略已成为一种经常评估治疗反应的新方法，因为满足特定目标的优化药物治疗是预防肠道损伤和逆转当前手术终身风险的关键 与严重IBD相关。尽管达标治疗策略尚处于起步阶段，但人们认识到，使用疾病特异性生物标志物进行频繁监测可能会改变结局，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，从而在出现临床明显症状之前提醒临床医生。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地评估正在进行的肠道炎症，并制定实现粘膜愈合的策略（通过内窥镜检查不存在肠溃疡），因为它是唯一确定的预测因素 持续缓解。现有的IBD生物标志物反映了非特异性炎症负荷，并且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，迫切需要准确检测内窥镜下炎症/愈合并涉及IBD发病机制的生物标志物，因为它将提供IBD特异性靶标以指导治疗。 在目标1中，我们将扩展我们以前的工作，并进一步定义多形白细胞（PMN）CD 64指数（CD 64表面表达的标志物）作为内镜严重程度和治疗反应的准确生物标志物。为了检验这一点，我们将纳入IBD患者谁已经提到结肠镜检查，并确定PMN CD 64指数的能力，以区分内镜严重程度评分（粘膜愈合，轻度，中度和重度）在克罗恩病和溃疡性结肠炎。我们还将确定PMN CD 64指数预测开始英夫利昔单抗治疗的IBD患者纵向队列的早期治疗反应和持续缓解的可能性的能力。在目的2中，我们将通过评估外周血和肠固有层来源的PMN的活性氧的产生，进一步探讨PMN CD 64表达升高对IBD肠上皮损伤的影响。此外，我们将测试一种新的治疗化合物对体外PMN功能的影响，因为小分子靶向激活的PMN，并将作为对当前治疗反应较差的IBD患者的替代治疗。