Patient-Oriented Research in Arginine Deficiency Syndromes

以患者为导向的精氨酸缺乏综合征研究

• 批准号: 10468085
• 负责人: Claudia R Morris
• 金额: $ 17.78万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468085
• 关键词: Absence of pain sensation; Academy; Accident and Emergency department; Acute; Acute Pain; Address; American; Amino Acids; Area; Arginine; Award; Blood; Child; Childhood; Clinical; Clinical Nutrition; Clinical Research; Clinical Sciences; Clinical Trials; Committee Members; Critical Care; Data; Death Rate; Development; Discipline; Drug Kinetics; Ear Acupuncture; Educational Curriculum; Educational workshop; Emergency Medicine; Emergency department visit; Enrollment; Environment; Event; Extramural Activities; Faculty; Fellowship; Follow-Up Studies; Fostering; Funding; Future; Goals; Grant; Hematology; Hospitalization; Hospitals; Hour; Hydration status; Infrastructure; Inpatients; Institutes; Integrative Medicine; International; Intervention; Lead; Leadership; Length of Stay; Master of Science; Medical Students; Medicine; Mentors; Mentorship; Mid-Career Clinical Scientist Award (K24); Narcotics; National Center for Complementary and Integrative Health; National Heart, Lung, and Blood Institute; Nephrology; Nitric Oxide; Nutritional; Nutritional Science; Nutritional Study; Pain; Patient Care; Patients; Pediatric Research; Pediatrics; Phase; Placebos; Postdoctoral Fellow; Product Approvals; Production; Program Development; Publications; Pulmonology; Randomized; Research; Research Activity; Research Personnel; Research Support; Resolution; Resources; Role; Safety; Schools; Scientist; Sickle Cell; Sickle Cell Anemia; Supplementation; Syndrome; TNFSF15 gene; Time; Training; Translational Research; Universities; Vasodilator Agents; acute care; arginine treatment; base; career; career development; certificate program; clinical practice; clinically relevant; dietary supplements; double-blind placebo controlled trial; evidence base; graduate student; improved; interest; leadership development; metabolome; mortality; neglect; new therapeutic target; next generation; novel therapeutics; opioid use; pain score; patient oriented research; pediatric department; pediatric emergency; phase III trial; product development; programs; randomized placebo-controlled clinical trial; recruit; skills; success; trend; undergraduate student; ward; willingness; women faculty

This K24 application entitled “Patient-Oriented Research (POR) in Arginine (Arg) Deficiency Syndromes” seeks 5 years of support for protected time to expand the principle investigator's (PI) mentoring activities, promote her career development & provide momentum to advance the applicant's research evaluating Arg therapy in sickle cell disease (SCD) and beyond. Arg is a nutritional supplement & obligate substrate for the production of nitric oxide, a potent vasodilator that becomes depleted during episodes of SCD-related pain and contributes to vaso- occlusion. The PI has completed a single-center randomized, double-blinded, placebo-controlled trial (RCT) of Arg therapy in 54 children with pain requiring hospitalization. She observed a reduction in opioid usage by over 54%, lower pain scores, and a clinically relevant trend towards decreased length of hospital stay in children who received 5 days of Arg therapy compared to placebo. She has an active research program that includes a FDA- sponsored Phase 2 RCT and a NHLBI-supported pharmacokinetics study of Arg therapy to treat SCD-related pain that is currently enrolling patients. The PI proposes to extend these studies to a definitive multi-center Phase 3 trial. Pain in SCD is the leading cause of hospitalizations, emergency room (ED) visits, missed school & is associated with an increased mortality rate. There are no current therapies to treat the underlying mechanisms of pain, with interventions limited to hydration and analgesia. The PI hypothesizes that Arg is a safe & inexpensive nutritional supplement with narcotic-sparing effects in pediatric SCD patients and pain. Her current and future study aims will determine the safety & efficacy of arginine therapy to reduce time to pain crisis resolution and total parenteral opioid use (mg/kg) in children with SCD & pain. This proposal will provide essential data for product development and will ultimately help gain FDA product approval for SCD if benefits of Arg therapy are confirmed in follow-up studies. Acute care of patients with SCD & pain in the ED is a neglected area of research. The results of this proposal may ultimately lead to a change in clinical practice for patients with SCD in both the ED & inpatient hospital wards. ED-based studies and novel therapies that target mechanisms of pain are needed in SCD. In addition, the PI is highly committed to performing POR focused on nutrition science & in growing her mentorship reach to include a diverse group of undergraduate's, graduate & medical students, post- doctoral fellows & junior faculty in clinical nutrition research, having mentored scholarly activity for over 35 mentees already during the course of her career. During the 5-year grant, the candidate will also participate in a number of mid-career leadership & mentorship courses, choosing curriculums that will help advance the candidate as an educational leader & mentor within academic medicine. The environment at Emory University is ideal to foster these goals, and will enhance the career development of the applicant as a mentor champion in integrative medicine in partnership with the Atlanta Clinical and Translational Science Institute, thereby enabling her to train mentees in the field and increase the pool of evidence-based integrative clinical scientists.

该K24申请题为“精氨酸（Arg）缺乏综合征的患者导向研究（Patient-Oriented Research，POR）”， 5年的支持保护时间，以扩大主要研究者（PI）的指导活动，促进她 职业发展和提供动力，以推进申请人的研究评估精氨酸治疗镰刀 细胞疾病（SCD）和其他疾病。精氨酸是一种营养补充剂，也是一种生产硝酸盐的专性底物 氧化物，一种有效的血管扩张剂，在SCD相关疼痛发作期间耗尽， 闭塞PI已经完成了一项单中心随机、双盲、安慰剂对照试验（RCT）， 精氨酸治疗需要住院治疗的疼痛患儿54例。她观察到阿片类药物的使用减少了超过 54%，疼痛评分较低，并且在以下儿童中具有缩短住院时间的临床相关趋势 与安慰剂相比，接受了5天的Arg治疗。她有一个积极的研究项目，包括食品和药物管理局- 申办的2期RCT和NHLBI支持的Arg治疗SCD相关性的药代动力学研究 目前正在招募患者。PI建议将这些研究扩展至确定的多中心阶段 3审判。SCD疼痛是住院、急诊室（艾德）就诊、缺课的主要原因 与死亡率增加有关。目前没有治疗潜在机制的疗法 的疼痛，干预措施仅限于水化和镇痛。PI假设Arg是安全的& 在儿科SCD患者和疼痛中具有麻醉保护作用的廉价营养补充剂。她现在的 未来的研究目标将确定精氨酸治疗减少疼痛危象时间的安全性和有效性 SCD和疼痛儿童的缓解和总胃肠外阿片类药物使用（mg/kg）。该提案将提供必要的 如果Arg的好处是， 治疗在后续研究中得到证实。在艾德急诊室对SCD和疼痛患者的急性护理是一个被忽视的领域 的研究。该提案的结果可能最终导致SCD患者临床实践的改变 在艾德和住院部的病房里。基于ED的研究和针对疼痛机制的新疗法 在SCD中需要。此外，PI高度致力于执行以营养科学为重点的POR 扩大她的导师范围，包括本科生，研究生和医科学生，后， 临床营养研究的博士研究员和初级教师，指导学术活动超过35年 在她的职业生涯中，已经有了一些学员。在5年资助期间，候选人还将参加一个 职业中期领导力和导师课程的数量，选择将有助于推进 候选人作为教育领导者和导师在学术医学。埃默里大学的环境 是理想的，以促进这些目标，并将加强职业发展的申请人作为一个导师冠军 与亚特兰大临床和转化科学研究所合作， 使她能够在该领域培训学员，并增加基于证据的综合临床科学家的人才库。