This R01 application is submitted to the funding opportunity announcement (PAR-13-195). Millions of children have surgery and anesthesia each year. Recent population studies have suggested that children who undergo anesthesia and surgery at an earlier age could have an increased risk for neurodevelopment disabilities (e.g., cognitive impairment). It is therefore urgent to perform studies in this new and under-investigated area: anesthesia- and surgery-induced cognitive impairment in children. However, thus far, no biomarker of such cognitive impairment has been developed. This gap in knowledge impedes the progress of such research. Therefore, we have proposed to develop and validate biomarkers in mouse models that can later be used to inform and effectively translate to clinical trials in children to study anesthesia- and surgery-induced cognitive impairment. Consistent with the notion that phosphorylated Tau (P-Tau) and neurogenesis contribute to cognitive function, our Preliminary studies show that anesthetic sevoflurane can increase levels of brain P-Tau, inhibit neurogenesis, cause cognitive impairment and increase blood Tau levels in young mice. Therefore, we hypothesize that Tau and P-Tau in blood and urine serve as the biomarkers for anesthesia- and surgery-induced cognitive impairment in young mice, and P-Tau inhibits the migration of neural progenitor cells (NPCs) by de-stabilizing their microtubules. Using both in vitro and in vivo approaches, and the innovative nano biosensor technology, we will test our hypothesis with three Specific Aims.
In Aim 1, we will use mass spectrometry, Western blot and nano biosensor technology to screen and then identify the elevation of Tau (soluble and insoluble) and specific P-Tau in mouse brain tissues and cerebrospinal fluid (CSF) following the particular anesthesia and surgery. We will also determine the associated cognitive function in the mice.
In Aim 2, we will use nano biosensor technology to show that there is elevation of Tau and specific P-Tau (same as those in the brain and CSF) in the blood and urine following the anesthesia and surgery in mice. Then, in the interventional validation studies, we will determine whether lithium and knockout (KO) of Tau (employing Tau KO mice) can mitigate the anesthesia- and surgery-induced cognitive impairment, and attenuate the elevation of Tau and P-Tau in the blood and urine of young mice. In the mechanistic validation studies (Aim 3), we will assess whether anesthesia- and surgery-induced increases in P-Tau will damage microtubule stability of the NPCs (in vitro) and slow down the NPCs migration (in vivo and in vitro). We will determine whether lithium and KO of Tau can rescue these effects. Translationally, this project would develop biomarkers for anesthesia- and surgery-induced cognitive impairment in young mice, which could later be used in children. Scientifically, this project would elucidate an innovative mechanism by which Tau affects NPCs migration. The results of this project would ultimately lead to safer anesthesia care and better postoperative outcomes for children.
This R01 application is submitted to the funding opportunity announcement [PAR-13-195 by National Institute of Child Health and Human Development (NICHD)]. We have proposed to develop and validate (interventional and mechanistic validation) Tau and phosphorylated Tau (P-Tau) in mouse blood and urine as biomarkers of anesthesia- and surgery-induced cognitive impairment in young mice. The findings of this project would ultimately lead to safer anesthesia care and better postoperative outcomes for children, which meet the mission of NICHD.
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