The Role of DIRAS Proteins in Neuronal Autophagy

Information

  • Research Project
  • 10128894
  • ApplicationId
    10128894
  • Core Project Number
    R21AG067282
  • Full Project Number
    1R21AG067282-01A1
  • Serial Number
    067282
  • FOA Number
    PA-19-053
  • Sub Project Id
  • Project Start Date
    9/30/2021 - 3 years ago
  • Project End Date
    5/31/2023 - a year ago
  • Program Officer Name
    WISE, BRADLEY C
  • Budget Start Date
    9/30/2021 - 3 years ago
  • Budget End Date
    5/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    9/21/2021 - 3 years ago

The Role of DIRAS Proteins in Neuronal Autophagy

Neurodegeneration is a hallmark of many neurodegenerative disorders. Although each neurodegenerative disease develops via distinct mechanisms, a feature common to many of them is dysfunctional autophagy. Autophagy, the fundamental process by which cells clear their contents, such as aggregated proteins and organelles, is the key to maintaining neuronal homeostasis. Mice deficient in autophagy develop massive neuronal loss and the accumulation of protein aggregates, suggesting that autophagy is important for neuronal function. There is also evidence, however, that some autophagic pathways are associated with cell death, an indication that the precise role of autophagy in neurodegeneration has not been fully resolved. DIRAS1/2/3 (DIRAS family, GTP-binding RAS-like proteins 1/2/3), the members of the Ras superfamily, regulate autophagy in cancer cells. DIRAS proteins regulate autophagy directly by being a part of the autophagy initiation complex and downregulating the mTOR signaling pathway. Importantly, the human genome contains Diras1, Diras2, and Diras3; whereas the mouse genome contains only Diras1 and Diras2, underscoring potential autophagic differences between human and mouse cells. In preliminary studies, we found the expression of DIRAS1 and 3 enhances the synthesis of autophagosomes and co-localizes with autophagosomes in cultured neurons. We hypothesize that, in neurons, DIRAS proteins can be modulated to increase neuroprotective autophagy, promote neuronal survival, and enhance the clearance of abnormal proteins and organelles. In the first aim, we will investigate if DIRAS proteins are involved in neuroprotective or neurotoxic autophagy in mouse and human neurons. In the second aim, we will investigate if DIRAS proteins regulate the specific forms of autophagy such as mitophagy and pexophagy. In the third aim, we will determine if DIRAS proteins regulate degradation of aggregation-prone proteins. These studies could form the basis for ?autophagy-enhancing? drug discovery, with applications to many neurodegenerative diseases in which protein clearance is dysfunctional.

IC Name
NATIONAL INSTITUTE ON AGING
  • Activity
    R21
  • Administering IC
    AG
  • Application Type
    1
  • Direct Cost Amount
    150000
  • Indirect Cost Amount
    84000
  • Total Cost
    234000
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    866
  • Ed Inst. Type
    SCHOOLS OF MEDICINE
  • Funding ICs
    NIA:234000\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    CMND
  • Study Section Name
    Cellular and Molecular Biology of Neurodegeneration Study Section
  • Organization Name
    UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
  • Organization Department
    NEUROLOGY
  • Organization DUNS
    800771594
  • Organization City
    HOUSTON
  • Organization State
    TX
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    770305400
  • Organization District
    UNITED STATES