Abstract

Our proposal involves the creation of a cuttingEedge, integrated multiEscale initiative aimed to reveal mechanistic insights into the cellular and functional traits that underlie the differential vulnerability of neurons in diseases affecting the nervous system. We propose an integrative in vivo genetic and functional approach centered on identifying and evaluating the impact of diseaseErelated genes in interconnected homeostasis networks, that may result in neuronal dysfunction due to decrease in connectivity and axonal degeneration. Scientific aims benefit from the development of new analytical approaches to model complex features related to neural vulnerability with an important functional genomic component. NBI hosts six researchers with expertise in molecular and systems neuroscience, genetics, neuropathology, behavior and functional genomics, which proposes a transEdisciplinary approach with selected genetic models and experimental strategies. This allows the functional analysis of disease genes and stress pathways to discover unidentified genes/networks/processes underlying specific pathological processes in neurons. Using novel experimental strategies, NBI also explores the morphological and functional correlates in neurons as possible traits related to disease. We aim to uncover transversal pathological events at different levels of complicity that may participate in neurodegenerative diseases, from molecular/cellular events to functional/behavioral alterations that could help explaining differential neuronal vulnerability in distinct pathologies. NBI will focus on a subset of diseases with already identified vulnerable and resistant neurons where the investigators of this initiative have demonstrated expertise, including Amyotrophic Lateral Sclerosis (ALS) and Parkinson ́s Disease (PD). In addition, to unravel common molecular mechanisms of degeneration in neuropathological conditions, we will use complementary experimental models, including axonal degeneration in mice and C. elegans models of neuronal cell death triggered by genetic stimuli. Genetic manipulation in mice will be performed for the study of stress networks in neuronal disorders relevant to humans. Overall, we aim to target a subset of homeostatic networks with genetic manipulation in model organisms of disease, and develop a series of bioinformatic, proteomic and functional genomics studies to identify new components of neuronal degeneration, and test whether these molecular network components relate to morphological and functional traits associated to neuronal degeneration. Moreover, NBI aims in the long term to apply this knowledge to design novel therapeutic strategies to target gene candidates and also identify novel disease biomarkers. NBI provides the necessary infrastructure, workforce and scientific targets to facilitate the pursuit of highElevel scientific research in a synergistic environment. NBI aims to establish a competitive international reference center for an in vivo genetic/functionalEoriented perspective to assess the role of diseaseErelated genes in neuronal function and dysfunction in the context of homeostasis networks with a broad impact in neurobiology and biomedicine.