Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY OF THE FUNDED PARENT GRANT AWARD Patients in intensive care units are at high risk for long-term health threats including cognitive impairment. The correlation was only recently revealed after large-scale follow-up cognitive assessments on intensive patient survivors after their discharge from the hospital. There are testimonials, reviews and calls-to-action on many critical care websites and in journal issues over the last 2-3 years on this public health crisis. However, the causative mechanisms that lead to abrupt cognitive impairment are unclear—they are not attributable to age, gender, relative brain hypoxia, anesthetics and sedatives. Nosocomial bacteria such as Pseudomonas aeruginosa impair endothelial cell function during the course of infection that culminates in acute lung injury. Recent studies implicate that after P. aeruginosa infection, endothelial cells produce and releases cytotoxic amyloids that are transmissible among cells. Having access to the endothelium of whole blood circulation, these cytotoxic amyloids likely propagate. In fact, the amyloids are detectable in the blood and cerebrospinal fluid of nosocomial pneumonia patients in intensive care units. Further, when applied to brain slices, the cytotoxic amyloids derived from endothelium impair neural activity and synaptic information transfer. This project takes advantage of vertically integrated approaches, ranging from the use of different bacteria stains and cultured cells, to in vitro brain slice recordings and in vivo animal behavior studies. The studies are designs to test the hypothesis that nosocomial pneumonias induce amyloid protein accumulation in CSF, resulting in LTP suppression and learning deficit. Altogether, studies systematically examine a possible lung-brain axis, where a primary lung infection induces production of cytotoxic amyloids that spread to the cerebrospinal fluid and contribute to cognitive impairment. This work addresses a novel mechanism underlying the end organ dysfunction that is evident during, and in the aftermath of, critical illness. Mechanistic insight into endothelium- derived cytotoxicity to brain function will reveal novel therapeutic approaches to prevent cognitive decline. PROJECT SUMMARY OF THE CURRENT ADMINISTRATIVE SUPPLEMENT APPLICATION Studies outlined in this project are designed to leverage a new humanized amyloid-β mouse. This mouse model was not available during preparation of the original submission and it will represent an important advance for the field to integrate this new mouse into our proposed studies.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
