Targeting FMNL2/Rho-GTPase Pathway for IOP Regulation in Glaucoma

Abstract: Primary open angle glaucoma (POAG) is a blinding disease world-wide, but for unknown reasons, persons from West Africa and of West African descent including African-Americans are at disproportionate risk. Dysfunction in aqueous humor outflow may lead to elevated IOP, which, if left untreated, can cause blindness. Yet, very little is known about this disease in African Americans. Therefore elucidation of IOP regulation in African Americans is a major hurdle that must be overcome before therapeutics for the treatment of POAG in this population can be developed. Genome-wide association study (GWAS), identified a unique genetic risk allele, the FMNL2 gene in African Americans with POAG. The FMNL2 gene encodes the formin- related protein-2 (FMNL2) that modulates TM cell actin stress fiber assembly, thus regulating TM contractility and IOP. Another protein, Cdc42-Rho GTPase regulates FMNL2 function. Contraction and relaxation of the TM cells help to regulate IOP. Collectively, these findings suggest that FMNL2 dysfunction is likely to alter actin stress fiber assembly and contribute to POAG. Given that scientific premise, the overall goal of this grant to elucidate the cellular, molecular and biochemical mechanisms that regulate IOP in African Americans aimed at identifying novel therapeutic targets for the treatment of glaucoma in that population. Our objective is to determine how FMNL2 regulates the TM cell contractile apparatus and thus modulates IOP in African Americans. Our global hypothesis is that dysfunction in FMNL2 in the African American population decreases aqueous humor outflow and results in the development of POAG. The specific aims will test these hypotheses: (Aim 1) Dysfunction of FMNL2 gene disrupts TM cell actin stress fibers and aqueous humor outflow, causing glaucoma in African Americans. (Aim 2) Cdc42-Rho GTPase signaling pathway regulates FMNL2-mediated TM contractility. In vitro and in vivo studies using human tissues will be utilized to investigate the mechanism of IOP regulation in African Americans. This project is novel and significant and its completion would for the first time, demonstrate in African Americans, 1) an IOP-regulatory mechanism, 2) a functional role for the FMNL2 gene in regulating physiological IOP and 3) a causative role for the FMNL2 risk allele gene in glaucoma. Identification of Cdc42-Rho GTPase/FMNL2 signaling pathway in African Americans will provide new therapeutic targets for the development of treatments for glaucoma in African Americans and other persons of West African descent that are at a high risk for development of the disease.