Chinyere Agbaegbu Iweka

The inability of axons to regenerate following injury is intriguing, and I wanted to understand the mechanisms that limit axon regeneration. I worked briefly with Dr. Mark Burns at Georgetown University, fascinated by his work, investigating the effects of Apolipoprotein E4 variant on blood brain barrier (BBB) integrity after traumatic brain injury (TBI). To facilitate characterization of the pathway that mediates BBB breakdown after a controlled cortical impact injury model of TBI, I developed a protocol to isolate cerebral microvessels that would enable detection of tight junction proteins. This work resulted in my first publication. To complement my training, I engaged in teaching Drugs, Brain and Behavior to undergraduate and graduate students. Funded by the NHLBI Intramural Research Training Award, I joined Dr. Herbert Geller’s lab to complete my graduate training, where I worked closely with Dr. Hiro Katagiri to investigate proteins that respond to chondroitin sulfate proteoglycans (CSPGs), a potent inhibitor of axon growth. I identified Phospholipid Phosphatase Related 1 (PLPPR1), a novel protein whose phosphorylation state was significantly altered in the presence of CSPGs. I also characterized the function of PLPPR1 in the CNS, discovering its modulatory effect on the Rho-GTPases that are also activated by CSPGs. This study was significant because PLPPR1 neuronal expression was able to impede CSPG inhibition of axon growth and resulted in a first author publication. Using Crispr-cas9 gene editing, I created a knock-out mouse model for PLPPR1. I discovered that global loss of PLPPR1 led to an increase in cortical and hippocampal dendritic spine density, enlarged lateral ventricles, hypoactivity, anxiety and impaired sensorimotor gating. I spent two years developing and optimizing a monoclonal, and then a polyclonal antibody targeting PLPPR1. Both were unsuccessful and prevented publication of my studies, however, I persevered and in turn acquired a plethora of skills, including new microscopy techniques such as STED and whole-mount tissue imaging, and behavioral assays. In parallel, to improve on my grantsmanship, I applied for and was awarded the Student Research Grant from Georgetown University. I presented my research at several conferences to improve on communicating my science, and participated in teaching workshops. I joined the NHLBI CBPC distinguished seminar series committee, where I invited guest speakers to present their work at our monthly seminars. I was elected junior co-chair for the Gordon Research Seminar, Cell Biology of the Neuron in 2018, where I procured funding support, selected poster and oral presentations, identified discussion leaders, invited a keynote speaker and panel discussion speakers, and successfully facilitated the meeting. Still fascinated by the mechanisms of CNS injury, I joined Dr. Katrin Andreasson’s lab at Stanford University for my postdoctoral training because I was intrigued by the myriad of non-neuronal cells that influence stroke severity. My long-term goal as an independent research scientist is to define how the circadian clock, through its regulation of metabolism and immune function, impacts stroke severity, and to translate that knowledge into effective strategies to improve stroke outcome. The circadian clock governs key components of metabolic pathways in immune cells, cell proliferation and expression of inflammatory molecules. I have since determined that genetic disruption of the circadian clock negatively impacts myeloid cell function and metabolism in aged mice. I have also determined that stroke impacts metabolic oxygen consumption in blood monocytes. My training has allowed me to develop expertise in models of stroke, immunology and metabolism and has provided a foundation in circadian biology. My research is crucial to understanding how circadian misalignment through aging and lifestyle, in terms of shift-work and jet-lag, can influence stroke pathophysiology.