About the Project
Increasing lines of study show the impact of systemic inflammation on neuroinflammation, resulting in accumulation of pathological factors and cognitive dysfunctions. However, its underlying mechanisms of how systemic inflammation is transmitted to neuroinflammation or how brain knows the systemic inflammation is still unclear. This is the holy grail question in neuroimmunology and neurodegeneration. We have adopted experimental model of laparotomy for post-operative cognitive dysfunction (POCD). We take intestine out from mice for massage and put back to abdomen without any surgical dissection. We have proved that effects of anesthetics are rather transient. Instead of anesthetics, our study showed that systemic inflammation elicits long-term effects to sustain activation of microglia/astrocytes, long-term tau phosphorylation and cognitive dysfunctions. Application of anti-inflammatory drug ibuprofen can revert all these effects. Therefore, this experimental model is ideal for us to investigate our key question in neuroimmunology.
Among different factors, we have recently obtained results showing that partial agonist of 42 nicotinic acetylcholine receptor (nAChR) can attenuate inflammatory responses, tau phosphorylation and cognitive dysfunctions. The current concept of “cholinergic anti-inflammatory pathway” often heavily focuses on 7nAChR. Less is known about 42 isoform. The objective of this proposed study is to elucidate the functions of 42nAChR on systemic inflammation and neuroinflammation. Our working hypothesis is that 42nAChR can be functioned as therapeutic target to attenuate systemic inflammation, neuroinflammation, tau pathology and cognitive dysfunctions. We will use molecular approach (cre-lox method) to specifically knockout 4 subunit so that no functional 42nAChR can be formed on macrophages, and then perform laparotomy. Some groups will have rescue experiments by in utero electroporation to give back 4 subunit. Next, we will use 42 agonists varenicline and TC2599 to investigate if agonists attenuate systemic inflammation, infiltration of macrophages (bearing green fluorescent protein), tau pathology and cognitive dysfunctions after laparotomy with or without varenicline/TC2599.
Faculty information, funding opportunities and application deadlines: https://www.findaphd.com/phds/program/biomedical-research-hku-li-ka-shing-faculty-of-medicine/?i586p4119
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