Patient-Oriented Research in Arginine Deficiency Syndromes

这份名为《精氨酸(Arg)缺乏综合征患者导向研究(POR)》的K24申请寻求 5年的支持保护时间，以扩大首席调查员(PI)的指导活动，促进她 职业发展&为申请者评估镰刀Arg疗法的研究提供动力 细胞性疾病(SCD)及以上疾病。精氨酸是一种营养补充剂，是生产硝酸盐的必需底物 氧化物是一种有效的血管扩张剂，在SCD相关疼痛发作时会耗尽，并有助于血管生成。 遮挡。PI已经完成了一项单中心随机、双盲、安慰剂对照试验(RCT) ARG治疗54例需住院治疗的疼痛患儿。她观察到阿片类药物的使用量减少了超过 54%，较低的疼痛评分，以及以下儿童住院时间减少的临床相关趋势 与安慰剂相比，接受了5天的精氨酸治疗。她有一个积极的研究项目，其中包括FDA- Arg治疗SCD相关疾病的2期随机对照试验和NHLBI支持的药代动力学研究 目前正在招收患者的疼痛。国际和平研究所建议将这些研究扩展到确定的多中心阶段 3个试验。SCD的疼痛是住院、急诊室(ED)就诊、旷课和IS的主要原因 与死亡率增加有关。目前还没有治疗这种潜在机制的疗法。 对于疼痛，干预措施仅限于水合和止痛。私家侦探假设Arg是一个安全的& 在儿童SCD患者和疼痛中具有节省麻醉效果的廉价营养补充剂。她目前的情况 未来的研究目标将确定精氨酸疗法的安全性和有效性，以减少出现疼痛危机的时间。 SCD和疼痛儿童的分辨率和阿片类药物总使用量(mg/kg)。这项提议将提供必要的 用于产品开发的数据，如果Arg的好处，最终将有助于获得FDA对SCD的产品批准 治疗在后续研究中得到证实。急诊室SCD和疼痛患者的急诊护理是一个被忽视的领域 研究的成果。这项建议的结果可能最终导致SCD患者的临床实践发生变化。 急诊室和住院部的病房。以ED为基础的研究和针对疼痛机制的新疗法 是SCD所需要的。此外，PI高度致力于开展以营养科学为重点的POR 扩大她的导师范围，包括不同的本科生、研究生和医学生、博士后和 临床营养学研究的博士生和初级教员，有超过35年的指导学术活动 在她的职业生涯中已经成为了导师。在为期5年的资助期间，候选人还将参加 职业生涯中期领导力和导师课程的数量，选择有助于推动 作为学术医学领域的教育领导者和导师的候选人。埃默里大学的环境 是促进这些目标的理想选择，并将促进申请者作为导师冠军的职业发展。 与亚特兰大临床和翻译科学研究所合作，从而 使她能够在该领域培训学员，并增加以证据为基础的综合性临床科学家队伍。

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.