The candidate is an MD/PhD trained clinical ophthalmologist with the career goal of investigating the mechanisms of glaucoma pathogenesis, using oculocerebrorenal syndrome of Lowe as a model disease. The career development plan will be jointly mentored by Dr. Jeffrey Travers and Dr. Zhong-yin Zhang, whose laboratories focus on the molecular signaling pathways of lipid mediators and protein phosphatases. The candidate's long-term aim is to understand the roles of phosphoinositide signaling in the eye, specifically regarding aqueous production and filtration, in order to identif novel targets for therapeutic development. Glaucoma is the second leading cause of irreversible blindness in the world and is the leading cause of blindness in African Americans. Elevated intraocular pressure (IOP) has been known to be a strong risk factor and remains the only target for intervention, but the mechanisms causing elevated IOP remain poorly understood. We have found evidence of an important regulator of vesicular trafficking in the eye that may control IOP. Lowe syndrome (OCRL1) is an X-linked disorder characterized by glaucoma and congenital cataracts, as well as brain and kidney diseases. The OCRL1 protein is an inositol polyphosphate 5-phosphatase that controls the levels of phosphoinositides, which in turn are important in vesicular trafficking. We propose to study the mechanism of OCRL1-mediated vesicular transport by examining the interaction between OCRL1 and kinesin motor proteins.
Our aims are to (1) characterize the distribution and expression of OCRL1 in human and mouse eyes, (2) determine whether OCRL1 mediates vesicular trafficking along microtubules by binding to kinesin family members, and (3) determine whether OCRL1 is required for the trafficking of apical membrane proteins in trabecular meshwork epithelium. The funding of this proposal will ultimately facilitate the discovery of new glaucoma therapies that can reduce the burden of blindness.
Glaucoma is a leading cause of irreversible blindness in the world, yet the mechanisms of glaucoma development remain poorly understood and the treatments are limited. This proposal outlines research to understand the mechanism of an inherited form of congenital glaucoma, in the hopes that this will provide insight and potentially lead to novel treatments for commonly seen forms of glaucoma.
|Luo, Na; Conwell, Michael D; Chen, Xingjuan et al. (2014) Primary cilia signaling mediates intraocular pressure sensation. Proc Natl Acad Sci U S A 111:12871-6|
|Adler, Jacob J; Johnson, Derrick E; Heller, Brigitte L et al. (2013) Serum deprivation inhibits the transcriptional co-activator YAP and cell growth via phosphorylation of the 130-kDa isoform of Angiomotin by the LATS1/2 protein kinases. Proc Natl Acad Sci U S A 110:17368-73|
|Kassa, Enoch; Elner, Victor M; Moroi, Sayoko E et al. (2013) Diffuse Berlin nodules: unusual presentation of ocular sarcoidosis. Br J Ophthalmol 97:1214, 1223-4|
|Luo, Na; Kumar, Akhilesh; Conwell, Michael et al. (2013) Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe. PLoS One 8:e66727|
|Luo, Na; Lu, Jingping; Sun, Yang (2012) Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish. Vision Res 75:98-107|
|Luo, Na; West, Callah C; Murga-Zamalloa, Carlos A et al. (2012) OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. Hum Mol Genet 21:3333-44|