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    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/2211", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
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        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/2206", 
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    ], 
    "amount": {
      "currency": "USD", 
      "type": "MonetaryAmount", 
      "value": "6504144"
    }, 
    "description": "DESCRIPTION (provided by applicant): Leber Hereditary Optic Neuropathy (LHON), the first inherited mtDNA disease identified, stereotypically presents as acute onset blindness in midlife and is one of the most common mtDNA mitochondrial disease phenotypes, >1 in 7000. LHON commonly results from missense mutations in mtDNA complex I (ND) genes, though rarer LHON mutations can occur in any mtDNA gene. LHON complex I gene mutations result in progressive retinal ganglion cell (RGC) and optic nerve degeneration with males being 2 to 5 times more likely to be affected than females and with a highly variable penetrance. Because of the unique tissue specificity of LHON, an animal model is required to investigate the neuronal, RGC and optic nerve physiology and pathology and to develop and test pharmacological and genetic therapies. After twenty years of development we have succeeded in isolating in the mouse mtDNA a mutation that is known to cause optic atrophy in humans (ND6 P25L) and in introducing this mtDNA mutation into the mouse female germ line in the homoplasmic state. This mouse manifests all of the features of LHON possible given the anatomical differences human and mice eyes. Analysis of synaptosomal ND6 P25L mitochondria has revealed a unique complex I defect in which ROS production is chronically elevated while ATP production is only minimally impaired. Hence, the primary causal factor in LHON appears to be chronic RGC oxidative stress. We now propose to use this pathophysiological insight and mouse model to further clarify the physiological consequences of LHON mutations for the RGC and optic nerve. We will then investigate the importance of nuclear-cytoplasmic interactions in generating the variable penetrance of LHON by combining the ND6 P25L mtDNA with a knockin missense mutation in an X- linked complex I gene and with an inducible mitochondrially-targeted catalase (mCAT). The former combination will permit investigation of the genetics of male bias and the later will allow confirmation of the importance of mitochondrial ROS in RGC and optic nerve toxicity and the role of nDNA antioxidant gene variation in modulating mutant mtDNA pathology. Our mouse model will also be used to test the efficacy of antioxidant drugs in inhibiting the onset of LHON and of benzofibrate in repairing mitochondrial and RGC oxidative damage through induction of mitochondrial biogenesis. Finally, we will prepare an AAV-mCAT vector for intra-orbital injection to transduce the mCAT catalytic antioxidant enzyme into the ND6 P25L RGC mitochondria in hopes of inhibiting RGC ROS production and optic atrophy. The AAV-mCAT experiments will be complemented by AAV transduction of allotopic mtDNA ND6 genes with either the universal genetic code or the mtDNA code. The former mRNAs will be translated on cytosolic ribosomes and the protein imported into the mitochondrion while the latter will carry RNA import signals to induce the uptake of the mRNA by the mitochondria and translation on mitochondrial ribosomes. Thus our mtDNA mutant mouse model of LHON has provided new insight into the pathophysiology of LHON and new avenues for therapeutics.", 
    "endDate": "2019-03-31T00:00:00Z", 
    "funder": {
      "id": "https://www.grid.ac/institutes/grid.416870.c", 
      "type": "Organization"
    }, 
    "id": "sg:grant.2555456", 
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        "value": [
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      }, 
      {
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        "type": "PropertyValue", 
        "value": [
          "R01NS021328"
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      }
    ], 
    "inLanguage": [
      "en"
    ], 
    "keywords": [
      "mouse eye", 
      "complex I", 
      "pathology", 
      "investigation", 
      "AAV-mCAT experiments", 
      "homoplasmic state", 
      "Mitochondrial Inborn Errors", 
      "X-", 
      "importance", 
      "time", 
      "ROS production", 
      "humans", 
      "genetic therapy", 
      "common mtDNA mitochondrial disease phenotypes", 
      "mtDNA", 
      "RGC ROS production", 
      "analysis", 
      "cytosolic ribosomes", 
      "genes", 
      "mouse model", 
      "chronic RGC oxidative stress", 
      "synaptosomal ND6 P25L mitochondria", 
      "mutations", 
      "ND6 P25L", 
      "mtDNA mutant mouse model", 
      "description", 
      "males", 
      "variable penetrance", 
      "unique tissue specificity", 
      "applicants", 
      "missense mutations", 
      "optic nerve", 
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      "onset", 
      "induction", 
      "MCAT", 
      "efficacy", 
      "mtDNA disease", 
      "females", 
      "therapeutics", 
      "knockin missense mutation", 
      "acute onset blindness", 
      "mRNA", 
      "male bias", 
      "ND6 P25L RGC mitochondria", 
      "mitochondrial ribosomes", 
      "ND6 P25L mtDNA", 
      "metabolism", 
      "mutant mtDNA pathology", 
      "allotopic mtDNA ND6 genes", 
      "features", 
      "antioxidant drugs", 
      "RNA import signals", 
      "Nd", 
      "rarer LHON mutations", 
      "confirmation", 
      "female germ line", 
      "former mRNAs", 
      "LHON complex I", 
      "progressive retinal ganglion cell", 
      "primary causal factor", 
      "benzofibrate", 
      "genetics", 
      "mtDNA codes", 
      "latter", 
      "new avenues", 
      "nuclear-cytoplasmic interactions", 
      "nDNA antioxidant gene variation", 
      "role", 
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      "optic nerve toxicity", 
      "unique complex I", 
      "RGC oxidative damage", 
      "mice", 
      "mitochondria", 
      "mitochondrial ROS", 
      "AAV transduction", 
      "mitochondria", 
      "years", 
      "optic atrophy", 
      "mtDNA mutations", 
      "anatomical differences", 
      "protein", 
      "mCAT catalytic antioxidant enzyme", 
      "LHON mutations", 
      "intra-orbital injections", 
      "mtDNA genes", 
      "former combination", 
      "midlife", 
      "optic nerve degeneration", 
      "hope", 
      "optic nerve physiology", 
      "physiological consequences", 
      "translation", 
      "pathophysiological insights", 
      "mitochondrial biogenesis", 
      "universal genetic code", 
      "uptake", 
      "ATP production", 
      "Leber's hereditary optic neuropathy", 
      "development", 
      "AAV-mCAT vector", 
      "pathophysiology", 
      "new insights"
    ], 
    "name": "Mitochondrial Inborn Errors in Metabolism", 
    "recipient": [
      {
        "id": "https://www.grid.ac/institutes/grid.239552.a", 
        "type": "Organization"
      }, 
      {
        "affiliation": {
          "id": "https://www.grid.ac/institutes/grid.239552.a", 
          "name": "CHILDREN'S HOSP OF PHILADELPHIA", 
          "type": "Organization"
        }, 
        "familyName": "WALLACE", 
        "givenName": "DOUGLAS C", 
        "id": "sg:person.012211015057.25", 
        "type": "Person"
      }, 
      {
        "member": "sg:person.012211015057.25", 
        "roleName": "PI", 
        "type": "Role"
      }
    ], 
    "sameAs": [
      "https://app.dimensions.ai/details/grant/grant.2555456"
    ], 
    "sdDataset": "grants", 
    "sdDatePublished": "2019-03-07T12:00", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
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    }, 
    "sdSource": "s3://com.uberresearch.data.processor/core_data/20181219_192338/projects/base/nih_projects_11.xml.gz", 
    "startDate": "1984-09-01T00:00:00Z", 
    "type": "MonetaryGrant", 
    "url": "http://projectreporter.nih.gov/project_info_description.cfm?aid=9253451"
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