rdf-syntax-grammar
mods:
  schema location: http://www.loc.gov/mods/v3 http://www.loc.gov/standards/mods/v3/mods-3-2.xsd
  title info:
    non sort: The
    title: Grisly World of MYOSIN-5A: Griscelli Syndrome Type 1 and the Search for an Effective Gene Therapy
  name:
    name part: Michaud, Danielle Renee
    role:
      role term: creator
    role:
      role term: author.
  name:
    name part: Nghiem, Peter
    role:
      role term: thesis advisor.
  name:
    name part: Texas A&M University
    role:
      role term: degree granting institution.
  type of resource: text
  genre: bibliography
  origin info:
    place:
      place term: txu
    date issued: 2023
    issuance: monographic
  language:
    language term: eng
  physical description:
    form: remote
    extent: 1 online resource.
  abstract: Griscelli Syndrome type 1 (GS1) is an ultra-rare, autosomal recessive human disease that affects vesicle and membrane trafficking caused by a mutation in the Myosin-Va gene. Myosin-Va is an unconventional motor protein that is highly expressed in the nervous system and skin. The use of a GS1 rat model with a spontaneously occurring point mutation in the Myosin-Va gene, which leads to a loss of functional MYO5A, allows for an in-depth analysis of GS1 and the development of potential therapies. Tissue from wildtype, heterozygous, and mutant rats were analyzed to identify molecular changes and markers to evaluate GS1 and therapeutic efficacy. Protein, RNA, immunostaining, and weight gain analyses determined that GS1 rats have a significantly decreased growth curve compared to non-mutant littermates. Furthermore, by postnatal day 30 GS1 rats demonstrated differential protein expression related to oxidative stress and expressed multiple different Myo5a mRNA splicing isoforms compared to wildtype. Though more work is needed to categorize the molecular phenotype of the GS1 rat, the data provides a starting point for evaluating therapeutic effectiveness. Two gene therapies were also developed to address the current lack of treatment for GS1: a mutation-correcting gene editing therapy and a gene replacement therapy. The gene editing therapy utilized CRISPR/Cas9 and a DNA minicircle to correct the mutation through homology independent targeted integration. Primary GS1 cell cultures and PC-12 cells were treated with the CRISPR/Cas9 paradigm and proof-of-concept editing was demonstrated. The gene replacement therapy was delivered in an integrating lentiviral vector with myc-tagged, rat Myosin-Va mRNA expressed under the human synapsin 1 promoter. GS1 rat striatal slice cultures were given lentiviral or sham treatment and total RNA demonstrated a significant increase in the Myo5a-myc-tag expression in high dose lentiviral treated cultures compared to control, though neither prot…
  note: by Danielle Michaud.
  note: "Major Subject: Biomedical Sciences"
  note: Includes vita.
  note: Doctor of Philosophy Texas A&M University 2022 https://hdl.handle.net/1969.1/197820
  note: Includes bibliographical references.
  note: Text (Dissertation)
  subject:
    topic: Major Biomedical Sciences
  subject:
    topic: MYO5A
  subject:
    topic: myosin-va
  subject:
    topic: Griscelli syndrome type 1
  subject:
    topic: Griscelli syndrome
  subject:
    topic: gene therapy
  subject:
    topic: gene replacement therapy
  subject:
    topic: CRISPR/Cas9
  subject:
    topic: gene editing
  identifier: https://hdl.handle.net/1969.1/197820
  record info:
    record content source: TXA
    record creation date: 240823
    record change date: 20240829173506.9
    record identifier: in00005468413
    language of cataloging:
      language term: eng