ABSTRACT Stroke is a major public health problem in the United States, where it is the 5th leading cause of death and the leading cause of adult disability. There is great need for translational and clinical research to develop interventions that prevent, treat, or enhance recovery after stroke. However, clinical trials require significant infrastructure, and the time and energy required to assemble this infrastructure for individual trials is a major barrier to progress. The NINDS Stroke Net was established in 2013 (we joined in 2018) as a national stroke trials infrastructure, designed to maximize efficiencies by centralizing regulatory and contractual agreements. With a single National Clinical Coordinating Center (NCC), a single National Data Management Center (DMC), and 29 Regional Coordinating Centers (RCCs) throughout the US, Stroke Net was established to efficiently recruit patients for stroke trials. The existing Stroke Net RCC28 Mid-America Regional Coordinating Center (MARCC) at Washington University School of Medicine (WU) and affiliated Barnes-Jewish Hospital (BJH), in collaboration with five other high-volume tertiary care Stroke Centers spans the Midwestern and Southern states of MO, KS, IL, TN, AR: St. Luke’s Hospital in Kansas City, MO; The Order of St. Francis Medical Center (OSF) in Peoria, IL; University of Tennessee Health Sciences in Memphis, TN; Cox Medical Center in Springfield, MO; and the University of Missouri in Colombia, MO. While not heavily represented in NIH clinical trials, these states have some of the highest stroke prevalence in the US. Missouri is ranked 19th in stroke mortality, Tennessee ranked 8th, Mississippi ranks 1st, Illinois 15th and Kansas 27th among all states according to 2020 CDC data. Since our last submission in 2018, the Mid-America Regional Coordinating Center (MARCC) at Washington University School of Medicine (WU) and affiliated Barnes-Jewish Hospital (BJH), has grown through enhanced attrition of low performing sites and addition of new sites including a large academic hub and five satellite high-volume tertiary care Stroke Centers. Each center has been carefully selected to serve as a tertiary care hub with large networks of referring hospitals, and has extensive experience in multi-center stroke trials. We consider MARCC a “Network of Networks”. Drawing from both rural and urban settings, the hospitals of MARCC admit over 7,500 stroke patients per year, including patients from diverse racial and socioeconomic backgrounds. Moreover, the MARCC collective group of stroke clinicians, investigators, coordinators, and scientists has successfully conducted Stroke Net trials, ranking 4th in overall Stroke Net Subject Enrollment from 2018-23 and ranking 4th in overall enrollment of Black Americans. We propose that MARCC will continue to perform as one of Stroke Net’s highest performing RCCs with the following specific aims: Aim 1. To maintain a seamless multi-state stroke trials infrastructure—the ...