The first step of vision takes place in the retina where light is captured by the outer segment of photoreceptor cells. This light-sensing organelle is a modified primary cilium with a unique architechture (hundreds of tightly stacked disc membranes enclosed by a plasma membrane) that contains an elite set of signaling and structural proteins. Since proteins are synthesized in the cell soma they require discrete intracellular trafficking mechanisms to be delivered to the outer segment. These trafficking mechanisms are critical for development and general maintenance of photoreceptors, as the outer segment is a dynamic structure that must be continuously renewed. Understanding mechanisms governing subcellular distribution of proteins remains a central unsolved problem in cell biology. As a new investigator, I will use my expertise in biochemistry, cell biology, molecular genetics, and retinal neurobiology to explore the mechanisms involved in delivering signaling and structural proteins to their final destination. My research will focus on investigating the outer segment trafficking of disc and plasma membrane proteins, as well as elucidating how outer segment proteins are segregated between the two functional membrane subdomains ? discs and plasma membrane. My proposal has broad implications to understanding the pathobiological processes underlying cases of retinal degenerative diseases and ciliopathy disorders.

Public Health Relevance

AND RELVANCE The mislocalization of signaling and structural outer segment proteins underlie some of the most severe types of inherited degenerative diseases of the retina, including the most frequently encountered cases of retinitis pigmentosa ? a blinding disease affecting nearly two million people worldwide. Elucidating the intracellular mechanisms guiding these proteins in healthy cells we, as a community, will be better positioned to develop new therapeutic strategies. Furthermore, understanding how the light-sensitive outer segment is normally built and maintained will be paramount as the community begins to explore new therapeutic approaches such as transplantation and stem cell technologies to treat patients with retinal diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Transition Award (R00)
Project #
3R00EY025732-04S1
Application #
9892591
Study Section
Program Officer
Neuhold, Lisa
Project Start
2018-03-01
Project End
2021-02-28
Budget Start
2019-09-01
Budget End
2020-02-28
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109