Patient-Oriented Research in Arginine Deficiency Syndromes

这份K24续订申请的题目是《精氨酸(ARG)缺乏患者导向研究(POR)》 综合征“寻求5年的额外支持，以维持主要调查员(PI)的受保护时间 指导活动，促进她的职业发展，并提供持续的动力，推动申请者的 评估ARG治疗镰状细胞病(SCD)及其他疾病的研究。精氨酸是一种营养补充剂& 专用于产生一氧化氮的底物，一氧化氮是一种有效的血管扩张剂，在发作时会耗尽 与SCD相关的疼痛。PI和她的受试者已经完成了几个随机、双盲、安慰剂- 美国和美国ARG治疗需要住院的SCD和疼痛儿童的对照试验(RCT) 尼日利亚。这些研究结合起来发现，ARG替代疗法(ART)具有节省阿片类药物的作用， 改善疼痛评分和心肺功能，减少止痛药使用和危机解决时间 与安慰剂相比，这与住院时间缩短有关。PI和他的同事还观察到 ART对改善儿童线粒体功能和降低氧化应激的剂量依赖性影响 患有SCD-Pain。最近NHLBI为利用儿科急救的多中心第三阶段随机对照试验提供资金 应用研究网络(PECARN)，PI计划进行权威研究-镰刀细胞病 使用精氨酸疗法(START)来确定ART的疗效和安全性。SCD中的疼痛是领先的 急诊室就诊和住院的原因，与死亡率增加有关。确实有 目前没有治疗急性疼痛的潜在机制的治疗方法，干预措施仅限于水合作用& 止痛药。PI假设ARG是一种安全、廉价、不含阿片类药物的营养补充剂 对患有SCD和疼痛的儿童的影响，在低资源环境中具有潜在价值。START审判将 为产品开发提供必要的数据，最终将有助于获得FDA对SCD的产品批准，如果 ART的好处得到了证实。这项提议的结果可能最终导致临床实践的改变。 对于SCD患者，NCCIH的目标是非药物治疗疼痛的战略优先事项。这个 Pi高度致力于执行专注于营养科学的POR&通过将她的导师范围扩大到 包括不同本科生、医学生、博士后研究员和初级教员，特别是 女性和临床营养研究中代表性不足的医生，指导了40多名实习生 在她的职业生涯中。在为期5年的拨款续期期间，候选人还将参加一些 领导力和导师课程，选择有助于促进候选人成为教育者的课程 学术医学领域的领导者和导师。埃默里大学的环境是实现这些目标的理想选择 并将促进申请者作为综合医学导师冠军的职业发展。 与佐治亚州临床和翻译科学联盟建立合作伙伴关系，使她能够在该领域培训学员 &增加以证据为基础的综合性临床科学家队伍。

This K24 renewal application entitled “Patient-Oriented Research (POR) in Arginine (ARG) Deficiency Syndromes” seeks 5 years of additional support for protected time to maintain the principle investigator’s (PI) mentoring activities, promote her career development & provide ongoing 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. The PI & her mentees have completed several randomized, double-blinded, placebo- controlled trials (RCT) of ARG therapy in children with SCD & pain requiring hospitalization in both the US & Nigeria. These studies combined found that ARG replacement therapy (ART) has opioid-sparing effects, improved pain scores & cardiopulmonary function, decreased pain medication use & time-to-crisis-resolution and was associated with a shorter hospital stay compared to placebo. The PI and colleagues also observed a dose-dependent impact of ART that improved mitochondrial function & decreased oxidative stress in children with SCD-pain. With recent NHLBI funding for a multicenter Phase 3 RCT utilizing the Pediatric Emergency Care Applied Research Network (PECARN), the PI plans to perform the definitive study - Sickle Cell Disease Treatment with Arginine Therapy (STArT) to determine the efficacy & safety of ART. Pain in SCD is the leading cause of emergency room (ED) visits & hospitalizations, associated with an increased mortality rate. There are no current therapies to treat the underlying mechanisms of acute pain, with interventions limited to hydration & analgesia. The PI hypothesizes that ARG is a safe & inexpensive nutritional supplement with opioid-sparing effects in children with SCD & pain, with potential value in low-resource environments. The STArT trial will provide essential data for product development & will ultimately help gain FDA product approval for SCD if benefits of ART are confirmed. The results of this proposal may ultimately lead to a change in clinical practice for patients with SCD and targets an NCCIH strategic priority of non-pharmacologic management of pain. The PI is highly committed to performing POR focused on nutrition science & in growing her mentorship reach to include a diverse group of undergraduates, medical students, post-doctoral fellows & junior faculty, particularly women & underrepresented physicians in clinical nutrition research, having mentored over 40 trainees throughout her career. During the 5-year grant renewal, the candidate will also participate in a number of leadership & mentorship courses, choosing curricula 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 Georgia Clinical & Translational Science Alliance, enabling her to train mentees in the field & increase the pool of evidence-based integrative clinical scientists.