The long-term goal of this project is to improve our understanding of the molecular mechanisms of inherited retinal diseases (IRDs) and to develop personalized treatments. Strikingly, ciliopathies have been identified as one of the major causes of IRDs with 25% of the known disease-causing genes involved in proper cilia formation and function in photoreceptor cells. However, despite the large number of retinal disease genes related to cilium function, the precise disease mechanisms remain largely unknown. We have recently discovered a novel subdomain of the photoreceptor connecting cilium (CC), named the photoreceptor- specific transition zone (PSTZ), which plays a critical role in CC stability and function. Establishment of the PSTZ depends on Spata7, a known LCA disease gene, and other members of the RPGR complex. In this proposal, we plan to utilize Spata7 as an entry point to better understand the function of this novel structure in the connecting cilium of photoreceptor cells.
Our Specific Aims are to:
Specific Aim 1 : Investigate the mechanism of PSTZ establishment Specific Aim 2: Determine the role of RPGR complex members in PSTZ structure and function Specific Aim 3: Determine the role of Spata7 in RPGR complex assembly and in establishment versus maintenance of CC structure and function Together these studies will provide a systematic evaluation of the PSTZ structure, key protein composition, regulation, and function, thereby providing novel insights concerning the molecular mechanisms of protein trafficking through the connecting cilium of photoreceptor cells. Given the central role primary cilia play not only in retinal disease, but also many other syndromic pathologies, these aims have the potential to make a high impact in our understanding of and ability to diagnose and treat human disease.

Public Health Relevance

Defects in proper connecting cilium formation and function in photoreceptor cells account for about 25% of inherited human retinal diseases, the leading cause of blindness in children and young adults. Our recent studies have identified a novel structure, named the photoreceptor-specific transition zone (PSTZ), that plays pivotal role in stabilizing the connecting cilium. Further detailed characterization and understanding of the structure and function of the PSTZ will provide invaluable insights into the mechanisms of retinal biology and disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY028970-01
Application #
9499797
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Neuhold, Lisa
Project Start
2018-09-01
Project End
2022-05-31
Budget Start
2018-09-01
Budget End
2019-05-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030