Project 3: Albayram

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PROJECT 3 – PROJECT SUMMARY Aberrant secondary immune activity after brain injury during neonatal life affects critical phases of brain development, with long-lasting behavioral abnormalities relevant to neurodevelopmental disorders. The most common form of brain injury in the preterm neonate is germinal matrix hemorrhage (GMH), which may display pathophysiological alterations relating to risk factors for atypical brain development. However, very little is known about how an aberrant secondary immune response that occurs and persists in the higher-order cortical and limbic regions of the developing brain following GMH leads to failure of compensatory synaptic and neuronal mechanisms and contributes to behavioral abnormalities. Recent studies have revealed a central role for complement in serving as a local immune recognition mechanism that promotes secondary injury after brain injury. Our preliminary data indicate a similar role for complement in propagating the pathogenic sequelae of GMH. Using a mouse model of GMH, we will investigate how complement dependent neuroinflammation in the neonatal brain following injury leads to failure of compensatory synaptic and neuronal mechanisms in primary cognitive centers of the brain. We will determine how complement activation impacts long-term behavioral changes relevant to neurodevelopment disorders, and we will investigate complement inhibition as a potential therapeutic approach to mitigate the pathogenic sequelae of GMH. Additionally, we will investigate the role of aberrant neuron/synapse elimination in the propagation of secondary brain injury, and specifically investigate a role for complement opsonin-complement receptor interactions in this process. The CNDD will provide me with critical support for the project through access to CNDD Cores and financial resources to support the research efforts, and the career development and mentoring activities will ensure future success in obtaining an NIH R01 within a 3-year period and a transition to an established investigator in the field of NDDs.