Mechanisms of RNA and Protein Dysregulations in ALS/FTD Associated with FUS and Ubiquilin 2

Information

  • Research Project
  • 10401555
  • ApplicationId
    10401555
  • Core Project Number
    R01NS110098
  • Full Project Number
    3R01NS110098-03S1
  • Serial Number
    110098
  • FOA Number
    PA-20-272
  • Sub Project Id
  • Project Start Date
    2/1/2019 - 5 years ago
  • Project End Date
    11/30/2023 - 3 months ago
  • Program Officer Name
    GUBITZ, AMELIE
  • Budget Start Date
    9/29/2021 - 2 years ago
  • Budget End Date
    9/28/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    03
  • Suffix
    S1
  • Award Notice Date
    9/21/2021 - 2 years ago
Organizations

Mechanisms of RNA and Protein Dysregulations in ALS/FTD Associated with FUS and Ubiquilin 2

Project Summary Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are increasing public health challenges, for which effective treatment is still lacking. At least two major themes that have emerged from the studies of ALS/FTD, concerning etiology related to both RNA metabolism and protein homeostasis. However, the mechanisms of RNA and protein homeostasis are not completely independent. UBQLN2 is a protein quality control factor that has been linked to ALS/FTD. Mutations in UBQLN2 have been linked to ALS/FTD, and UBQLN2 immunoreactivity is found in ALS/FTD and other neurodegenerative conditions. We have identified a role for UBQLN2 in antagonizing the aberrant phase transition and stress granule formation of mutant FUS, behaviors that potentially disrupt the RNA- processing functions of FUS and lead to neurodegeneration. The induced pluripotent stem cells (iPSC)-derived models have become instrumental experimental systems for study the pathological mechanisms and therapeutic interventions for neurodegenerative diseases including Alzheimer?s disease and related dementias (ADRD). Here we will characterize iPSC lines that harbor ADRD-related mutations in order to develop better ADRD disease models. The project is aimed at deep quality control and molecular phenotyping of the iPSC lines to generate predictable and reliable models. The outcome of the studies will not only provide clinically relevant models for this form of neurodegeneration diseases such as ALS/FTD but also generate insights into the pathogenic mechanisms as well as therapeutic applications for the devasting diseases.

IC Name
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
  • Activity
    R01
  • Administering IC
    NS
  • Application Type
    3
  • Direct Cost Amount
    255199
  • Indirect Cost Amount
    162689
  • Total Cost
    417888
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    853
  • Ed Inst. Type
    SCHOOLS OF PUBLIC HEALTH
  • Funding ICs
    NIA:417888\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
  • Study Section Name
  • Organization Name
    JOHNS HOPKINS UNIVERSITY
  • Organization Department
    BIOCHEMISTRY
  • Organization DUNS
    001910777
  • Organization City
    BALTIMORE
  • Organization State
    MD
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    212182680
  • Organization District
    UNITED STATES