Investigation of the molecular basis of rod and cone photoreceptor structure

Information

  • Research Project
  • 9698684
  • ApplicationId
    9698684
  • Core Project Number
    R01EY025291
  • Full Project Number
    3R01EY025291-03S1
  • Serial Number
    025291
  • FOA Number
    PA-13-302
  • Sub Project Id
  • Project Start Date
    5/1/2016 - 8 years ago
  • Project End Date
    4/30/2020 - 4 years ago
  • Program Officer Name
    NEUHOLD, LISA
  • Budget Start Date
    5/1/2018 - 6 years ago
  • Budget End Date
    4/30/2019 - 5 years ago
  • Fiscal Year
    2018
  • Support Year
    03
  • Suffix
    S1
  • Award Notice Date
    6/8/2018 - 6 years ago
Organizations

Investigation of the molecular basis of rod and cone photoreceptor structure

? DESCRIPTION (provided by applicant): Vertebrate sight and human visual health depend upon the membranous architecture of rod and cone photoreceptor outer segments (OSs). A broad variety of sight-robbing diseases is associated with defects in OS architecture; however, neither the underlying disease etiologies, nor the fundamental biology of the receptor cells is well understood. In particular, the molecular mechanisms responsible for generating and stabilizing the structure of mature rod and cone OS disks are not yet known. The long-term goal of this research is to define OS architecture and renewal in sufficient detail to explain how defects generate retinal disease and design effective therapeutic strategies. The current goal is to determine how peripherin-2/rds (P/rds) functions as an organizer for OS membranes. This integral membrane tetraspanin acts in an essential, though mechanistically uncertain fashion to support OS architecture for both rods and cones, and inherited mutations in P/rds cause a broad range of progressive diseases, including retinitis pigmentosa and macular degenerations. The first Aim of this study will determine the importance of known protein structural/regulatory determinants for P/rds induction of highly curved membranes. The second Aim will test the hypothesis that the P/rds C-terminus is normally membrane associated via partitioning of an inducible amphipathic helix that can function to tether OS disk rims together. The third Aim will test the hypothesis that pathogenic mutations in the P/rds C-terminal domain can preferentially impact cone photoreceptors. Successful completion of the work proposed would improve knowledge of P/rds protein structure-function, clarify how P/rds can generate high curvature membranes to form and stabilize OS disks, and would provide a mechanistic basis for understanding how pathogenic mutations in P/rds preferentially affect cone (vs. rod) photoreceptors. The work could also make a positive impact by suggesting new strategies for managing progressive retinal degenerations that result from primary pathologies in OS structure.

IC Name
NATIONAL EYE INSTITUTE
  • Activity
    R01
  • Administering IC
    EY
  • Application Type
    3
  • Direct Cost Amount
    63677
  • Indirect Cost Amount
    0
  • Total Cost
    63677
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    867
  • Ed Inst. Type
    ORGANIZED RESEARCH UNITS
  • Funding ICs
    NEI:63677\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    BVS
  • Study Section Name
    Biology of the Visual System Study Section
  • Organization Name
    OAKLAND UNIVERSITY
  • Organization Department
    NONE
  • Organization DUNS
    041808262
  • Organization City
    ROCHESTER
  • Organization State
    MI
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    483094422
  • Organization District
    UNITED STATES