Catalyst Awardee

Project Description

Improving brain proteostasis as a strategy to reduce the adverse effects of psychosocial stress on the cognitive decline of the elderly


Mei-Li Díaz Hung, PhD | Biomedical Neuroscience Institute; Claudio Hetz, PhD; Giovanni Tamburini, MS; Diego Arriagada, MS; María José Altamirano, MV
Competition Sponsor: Chile Agencia Nacional de Investigacion y Desarrollo
Awardee Year: 2022

Prolonged exposure to stress could result in deleterious effects to the brain function, reducing our cognitive capacity, impacting the functions involved in learning and memory. Exposure to stress with concomitant elevation of glucocorticoids has been implicated in the acceleration and/or exacerbation of cognitive deficits in elderly subjects. A tight control of protein homeostasis (termed proteostasis) is a central factor driving molecular events linked to synaptic plasticity and cognition, a process seriously affected during aging. In this project we propose to use a gene therapy strategy to manipulate XBP1, a master regulator of the UPR, coupled to the exposure of animals to chronic stress paradigm in young and middle-aged mice to prevent o revert the adverse effect of stress on cognition. We propose the use of gene therapy to improve resilience during process aging, which could be revolutionary. We hypothesize that chronic psychosocial stress impairs neuronal proteostasis, accelerating cognitive decline during aging, and artificial enforcement of brain UPR using adeno-associated virus (AAV-XBP1s) reduces the adverse behavioral effects of stress. These experiments will allow us to define the specific impact of the ER proteostasis network in coping and recovering from the adverse effects of environmental stress during aging. Thus, the development of this project will allow us to i) provide a theorical value for mental health interventions during aging and offer a direct solution to health problems that affect millions of people in the world ii) generate intellectual property and a commercial patent iii) position Chile in the global Biotechnology Industry market.

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