BH3- Only Proteins and Cellular Bioenergetic in the Control of Neuronal Survival and Cell Death: Role in Ischaemic Injury and Neurodegeneration

• Ireland

Science Foundation Ireland

3471112.00

01-01-2009

60

• Neurodegenerative disease in general

Neuronal Apoptosis, Excitotoxicity, Ca2+ Mediated Cell Death, ER
Stress, Proteasomal Stress, Ischemic Stroke, Neurodegeneration, BH3 Only
Proteins, BIM, PUMA, Mitochondria, Bioenergetics, Computational Biology, Systems Biology

The proposed programme will investigate key mechanisms underlying neuronal survival
and cell death in response to ischemic brain injury and during chronic neurodegeneration.
Based on previous research, we will investigate the role of pro-apoptotic BH3 Only
Proteins and cellular and mitochondrial bioenergetics in cell death and cell survival
decisions in response to neuronal Ca2+ overloading, endoplasmic reticulum stress,
proteasomal inhibition, and oxygen/glucose deprivation. These studies will be conducted
using established neuronal cell culture and organotypic slice culture systems, and key
findings will be translated into appropriate animal models. Building on our expertise
and previous investments in single-cell analysis, quantitative microscopy, and
computational biology, we aim to identify key decision and intervention points using both
hypothesis-driven and systems-driven research approaches. These investigations will
generate novel therapeutic targets and prognostic tools for drug discovery, which could
ultimately benefit the treatment of ischemic brain injury, chronic neurodegeneration, and
potentially other disorders of inappropriate cell death signalling.

Stroke and age-related brain disorders are leading causes of death and disability
which, with increasing life expectancy in Ireland, impose a growing economic and
societal burden. Current treatment regimes are limited in their effectiveness, partially
due to a lack of understanding of why nerve cells die or survive during brain injury.
This research programme tackles this important question by investigating a family of
genes that mediate stress-induced cell death, and by addressing the role of reduced
energy supply during brain injury. The programme involves an established collaboration
with SIEMENS engineers who will bring essential computational approaches into this
research programme that facilitate the analysis of biological networks, and accelerate the
identification of new targets for future therapy. The research programme also allows for the
development and dissemination of new, Irish born, technology by integrating the activities
of LUXCEL Biosciences, a pioneer in oxygen sensing technologies, into the research
programme.

• Basic research