Principal Investigators

    KALB, ROBERT G

    Institution

    CHILDREN'S HOSP OF PHILADELPHIA

    Contact information of lead PI

    Country

    USA

    Title of project or programme

    Cytohesins, ARF GTPases and Neurodegeneration

    Source of funding information

    NIH (NINDS)

    Total sum awarded (Euro)

    € 597,247.71

    Start date of award

    01/06/2016

    Total duration of award in years

    2

    The project/programme is most relevant to:

    Motor neurone diseases

    Keywords

    Guanosine Triphosphate, Toxic Actions, Nerve Degeneration, Amyotrophic Lateral Sclerosis, Guanine Nucleotide Exchange Factors

    Research Abstract

    Abstract In vitro and in vivo models of neurodegenerative disease such as Amyotrophic Lateral Sclerosis (ALS) have provided glimpses into the biological processes that go awry in these disorders. Current thinking indicates that major pathophysiologic processes include protein misfolding and accumulation, endoplasmic reticulum stress, dysfunctional intracellular trafficking, excitotoxicity, mitochondrial dysfunction, neuroinflammation, and abnormal RNA processing. The ARF family of GTP’ases are a phylogenetically- conserved family of proteins involved with membrane traffic, lipid metabolism/signaling, actin remodeling, and lipid droplet formation. Based on the apparent overlap between ALS pathophysiology and some of the biological actions of ARFs, we wondered if ARF signaling modified models of ALS. In recently published work we find that blocking activity of cytohesins (“Cy’s”, ARF guanine nucleotide exchange factors) is neuroprotective. Understanding the cell biological mechanism of this observation is problematic because of the pleiotropic actions of Cy’s and ARFs. The path forward will be facilitated by determining the specific Cy and specific ARF involved in this process as this will guide us to the relevant cell biological process. To this end, in specific aim #1, experiments will be undertaken to determine if inhibition of an individual Cy confers protection against the toxic actions on motor neurons of mutant SOD or mutant TDP43. In specific aim #2, experiments will be undertaken to determine if inhibition of an individual ARF confers protection against the toxic actions on motor neurons of mutant SOD or mutant TDP43. Identification of the specific Cy/ARF pair that upon disabling is neuroprotective will be the launching pad for insight into mechanisms and potential therapeutic targeting.

    Lay Summary

    Narrative Proteins must fold into a proper three-dimensional shape to function normally in cells and misfolded proteins accumulate in nerve cells in adult onset neurodegenerative diseases. In this proposal we will identify genes and molecular pathways that reduce the burden of misfolded proteins, or their toxic actions, on neurons

    Further information available at:

Types: Investments > €500k
Member States: United States of America
Diseases: Motor neurone diseases
Years: 2016
Database Categories: N/A
Database Tags: N/A

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