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 unique in that it is a modified primary cilium that is composed of a specialized group of proteins involved in visual signal transduction. These proteins are synthesized in the cell soma and use 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. During the mentored phase I will complete three ongoing, interconnected projects that address how intracellular trafficking mechanisms are established and required for outer segment stability. First, I will decipher how the features of rhodopsin and its trafficking pathway are necessary for outer segment formation. Second, I will determine the scope of Arf4 involvement in rhodopsin trafficking to outer segments by analyzing a rod-specific Arf4 knockout mouse. Finally, I will identify and refine active targeting domains encoded within proteins localized in the outer segment. This comprehensive approach will facilitate my transition to the independent phase, in which I propose to elucidate how signaling proteins are segregated between the disc and the plasma membrane subdomains of the outer segment. My proposal has broad implications for understanding the pathobiological processes underlying cases of inherited retinal degenerations, many of which are caused by mutations affecting protein trafficking to the photoreceptor outer segment.

Public Health Relevance

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 #
5R00EY025732-04
Application #
9656144
Study Section
Special Emphasis Panel (NSS)
Program Officer
Neuhold, Lisa
Project Start
2018-03-01
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
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