Abstract: 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. 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 undergraduates, medical students, post-doctoral fellows & junior faculty 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, ...