Glaucoma is a major cause of blindness. It involves death of retinal ganglion cells and degeneration of the optic nerve. High intraocular pressure (IOP) is frequently associated with glaucoma. It is thought to be an important causative factor. The multiple factors interacting with IOP to cause damage are not clearly defined. The PI's long term objective is to identify and characterize genetic factors that contribute to elevated IOP and glaucoma. Recent advances make the identification of chromosomal regions involved in glaucoma more practical than ever before. The task of identifying the specific causative genes in humans and of proving their relevance, however, remains difficult. using mice as an animal model, the PI will take advantage of the ability to alter endogenous genes to test their functional significance for IOP regulation and glaucoma. To start this process the investigator has developed a reliable method to measure IOP in mice. The PI proposes to use genetically altered mice to assess the importance of the natriuretic peptide system for IOP regulation. The natriuretic peptides (NPs) are important in regulating body fluid volume, and in moving fluid between compartments. The NPs and their receptors (NPRs) are present in the eye. They occur in the ciliary epithelium that produces the ocular fluid (aqueous humor) and in cells of the aqueous humor drainage (outflow) pathway. Available evidence suggests that the NPs act to decrease IOP. At least part of this effect seems to result from NP-stimulated increases in aqueous outflow. A genetic deficiency of NPs or NPRs, thus, may result in increased IOP and could be one of the multiple facotrs contributing to elevated IOP and glaucoma. In support of this, preliminary studies suggest that mice that are homozygous for a mutation that diminishes production of both atrial natriuretic peptide and brain natriuretic peptide have significantly increased IOP. To determine the extent to which this mutation alters IOP, and to determine the consequences of genetic deficiencies in other components of the natriuretic peptide system, the PI proposes to test: 1. If a genetic deficiency of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) can cause increased IOP. 2. If a genetic deficiency of natriuretic peptide receptor 1 (NPR1) can cause increased IOP. 3. If a genetic deficiency of C-type natriuretic peptide (CNP) can cause increased IOP. These studies should determine if these NP system genes are reasonable candidates to contribute to human glaucoma. They are likely to increase understanding of the roles of various natriuretic peptides and natriuretic peptide receptors in IOP homeostasis.
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