Rest/Active Phase Specificity of APOE4 and Inflammation on Respiratory Plasticity

PROJECT SUMMARY This K99/R00 Pathway to Independence Award is designed so that the candidate will achieve her long-term goal of establishing an independent research career focused on the neural control of breathing. Specifically, I will study how genetic factors influence mechanisms of respiratory motor plasticity. This proposal has been tailored to supplement the candidate’s background in neuroscience and respiratory physiology with additional knowledge and technical skills necessary for targeted gene manipulations and cell-specific molecular analysis. These skills will be applied to a well-studied model of respiratory motor plasticity known as phrenic long-term facilitation (pLTF), a prolonged increase in phrenic motor output triggered by moderate acute intermittent hypoxia (mAIH). Hypoxia-induced adenosine release from spinal glia initiates signaling mechanisms that undermine serotonin- driven pLTF. Factors that increase spinal adenosine levels, such as inflammation and the daily active phase, further constrain pLTF. Understanding how specific factors undermine phrenic motor plasticity has the potential to reveal molecular targets for precision interventions, a necessary step to optimize therapeutic efficacy of AIH in ongoing clinical trails to preserve/restore breathing ability in people with spinal cord injury and ALS. Apolipoprotein (APOE) alleles (E2, E3 and E4) predict whether healthy individuals express respiratory plasticity, although little is known concerning how it does so. Exciting preliminary data lead us to hypothesize that APOE4 undermines pLTF through an adenosine-dependent mechanism, particularly during the rodent active (nocturnal) phase, when spinal adenosine levels are high (Aim 1). ApoE4 biases microglia (a regulator of neuroplasticity) towards a pro-inflammatory state and inflammation abolishes pLTF by a spinal adenosine mechanism. Since both hypoxia and inflammation stimulate phrenic motor neuron-microglia signaling and elicit ATP/adenosine release, we propose that neuronal ApoE4 exacerbates phrenic motor neuron-microglia signaling, increasing spinal adenosine levels. When combined with adenosine levels that are already elevated in the daily active phase, pLTF is suppressed or abolished (Aim 2). Since nearly all lung and CNS disorders are associated with systemic and/or neural inflammation, the candidate will determine how a widely-studied model of inflammation (lipopolysaccharide; LPS) and ApoE4 interact in disrupting phrenic motor neuron-microglia communication in the daily rest vs active phases (Aim 3). The aims of this proposal are supported by abundant preliminary data and will yield novel information providing a fundamental framework for understanding how ApoE4 and inflammation disrupt respiratory motor plasticity. A dedicated mentoring committee of successful scientists will contribute invaluable expertise and guidance, expanding the candidate’s scientific background and productivity while also providing a strong foundation for success in achieving her scientific and career goals.