R01NS084604 National Institute of Neurological Disorders and Stroke (NINDS) (3/1/2014 – 2/28/2019)
DESCRIPTION (provided by applicant): Brain damage after cerebral hypoxia-ischemia is a major contributor to death and disability in children. In fact, quality survival after brain injuryis the greatest irreversible unmet need in critically ill children, including those with co-morbiditie such as cancer. The most common cause of cerebral hypoxia-ischemia in infants and children is as a consequence of cardiac arrest; although, cerebral hypoxia-ischemia negatively impacts quality of life in many other diseases including traumatic brain injury, stroke, intracerebral hemorrhage, and inflammatory and neurodegenerative diseases. Disheartening morbidity or mortality with survivability directly related to the degree of hypoxic-ischemic encephalopathy (HIE)-and perceived futile care, are the most common outcomes. Robust therapies to prevent and/or treat cerebral hypoxia-ischemia after cardiac arrest and as a consequence of a host of other diseases are urgently needed. At the crux of hypoxia-ischemic injury, are mitochondria. After hypoxia-ischemia damaged mitochondria produce toxic free radicals that directly attack vital cellular constituents; are at the convergence of several critical cell death pathways; and ar powerful mediators of inflammation. Central to all of these potentially pathological mechanisms is the supraphysiologic generation of reactive oxygen species (ROS), making mitochondria-generated ROS a logical and potentially impactful therapeutic target for HIE. To date, strategies targeting ROS have focused on free radical scavengers or replacing endogenous antioxidants to quench these highly reactive compounds. Disappointingly, these strategies have not translated into efficacious treatments. A paradigm-shifting approach is needed, e.g. preventing generation of ROS, rather than attempting to quench them. Novel compounds that target mitochondria include "therapeutic payloads" conjugated with: i) chemical moieties utilized in antibacterial agents that have a high affinity for mitochondrial membranes, taking advantage of the shared ancestry between mitochondria and bacteria; or ii) a cationic moiety, taking advantage of electrophoretic properties and mitochondrial membrane potential. As a multidisciplinary team, we are in the fortunate position to synthesize and develop a library of promising nitroxide-based, mitochondria-targeting therapeutics that function primarily as electron scavengers-in contrast to traditional antioxidants, thus preventing formation of ROS. Furthermore, we are uniquely poised to test these powerful mitochondria- targeting therapies in our models of hypoxia-ischemia in the developing brain, including our clinically relevant model of pediatric asphyxial cardiac arrest. The aim of this research is to synthesize and develop novel mitochondria-targeting therapeutics, toward meaningfully improving neurological outcome and quality of life in infants and children suffering from cerebral hypoxia-ischemia.
PUBLIC HEALTH RELEVANCE: Quality survival after brain injury is the greatest unmet need in critically ill children. A major contributor to this unmet need is devastating morbidity and mortalty caused by hypoxia-ischemia. This research aims to synthesize and develop novel mitochondria-targeting therapeutics, toward meaningfully improving neurological outcome and quality of life in infants and children suffering from cerebral hypoxia-ischemia.