Director, USC Institute for Genetic Medicine
Professor of Cell & Neurobiology and Ophthalmology
Keck School of Medicine
- Eye Diseases
- Neural and Neuroendocrine Cancers
Research OverviewThe Matrix Metalloproteinase (MMP) family of tissue remodeling enzymes has been the main focus of research in the Fini Lab. The group has been interested in biological and disease roles for MMP1 and MMP9, as well as mechanisms of MMP9 gene regulation. Based first at Harvard, then Tufts, then University of Miami, the lab has contributed to a number of areas, including mechanisms of corneal repair, remodeling and ulceration, maintenance of the corneal epithelium, glaucoma, eye development, cancer, brain trauma, and angiogenesis.
In February 2008, Dr. Fini moved to the Keck School of Medicine as the Vice Dean for Research. She was appointed as Director of the USC Institute for Genetic Medicine in July 2009. In June 2012, Dr. Fini stepped down from the research dean position to devote more time to the IGM department and the research programs of her lab, with a renewed direction towards therapeutic applications.
Current research focuses on disease mechanisms and therapeutic potential of proteins identified in two broad-based discovery screens: 1) a yeast-two-hybrid screen for interacting partners of MMP9 found in the cornea, and 2) a pharmacogenomic genome-wide association study (GWAS) for genetic variants that associate with steroid-induced ocular hypertension.
The yeast two-hybrid screen identified Clusterin, an extracellular glycoprotein expressed prominently at fluid-tissue interfaces. It has been known for many years that Clusterin is highly expressed in the cornea and is one of the major components of the tears, however, its specific role in this location has remained a mystery. The Fini lab recently made a breakthrough when it was discovered that Clusterin binds tightly to MMP9 and inhibits its activity. MMP9 was shown to be central to ocular surface barrier damage due to desiccating stress in a preclinical mouse model for dry eye disease. In a study currently underway, the Lab has demonstrated the remarkable capacity of Clusterin to protect the ocular surface barrier in this mouse model. Impressively, Clusterin also completely ameliorates pre-existing barrier disruption. These findings may be of very high impact, as there is currently only a single pharmaceutical approved by the Federal Drug Administration (FDA) for dry eye, a disease of aging that affects the eyesight and quality of life for millions of Americans. Clusterin might also serve to protect against disruption of the ocular surface barrier due to other causes, including those related to contact lens wear, refractive surgical procedures, and nerve-related disorders.
The GWAS identified GPR158, a novel G protein-coupled receptor (GPCR). GPR158 is highly expressed in the brain, retina and neuroendocrine tissues. The Fini Lab’s 2013 paper on GPR158 was one of two published within a few months of one another, independently providing the first characterization of GPR158. This paper also implicated GPR158 in ocular hypertension leading to glaucoma. Now in second paper, the group implicates GPR158 in prostate cancer.
The plasma membrane activity of the typical GPCR family member is very approachable by pharmaceutical targeting, and GPCRs currently serve as the targets for ~40% of marketed drugs. However, GPR158 does not appear to function as a typical GPCR, instead exhibiting two novel activities, one at the plasma membrane and one in the nucleus.
First, GPR158 at the plasma membrane appears to enhance the activity of other GPCRs. With respect to ocular hypertension, this means it may have the unique and therapeutically valuable capacity to reduce intraocular pressure (IOP) by controlling relevant GPCRs as a group, each of which is currently being targeted by a specific drug.
Second, the lab discovered an unusual nuclear activity whereby GPR158 controls gene expression and cell proliferation. Significantly, this activity promotes growth of prostate cancer cells in the absence of androgens and androgen receptor. Further, the plasma membrane activity of GPR158 appears to promote neuroendocrine differentiation in a bifunctional switch mechanism. Given the emerging importance of neuroendocrine prostate cancer in patients with resistance to next-generation androgen receptor-targeted therapies, GPR158 presents significant potential for high impact as a novel drug target.