PROTEOGLYCANS AND INHERITANCE OF OPEN-ANGLE GLAUCOMA

Primary open-angle glaucoma (POAG) is a leading causes of blindness
and identification of a gene for this condition would have profound
implications. POAG results from impaired aqueous humor outflow in
the eye. Trabecular meshwork proteoglycans are the most likely
candidates for regulating the outflow resistance of the aqueous
humor and, thus, are one of the determinants of intraocular
pressure. Identification of these proteoglycans is important in
understanding the nature and mechanism of the regulation of aqueous
outflow. This proposal seeks to complete our identification and
characterization of trabecular proteoglycans. This work will be
facilitated by the availability of new proteoglycan sequences
allowing production of specific core protein peptide antibodies and
oligonucleotides. A trabecular meshwork cDNA expression library
will be screened by peptide antibodies and/or by degenerate
oligonucleotides made against the unique trabecular meshwork
proteoglycan sequences identified by us. We will localize each of
these proteoglycans in the trabecular meshwork using
immunohistochemistry. These complementary approaches will allow the
identification of the important trabecular meshwork proteoglycans. Based on several independent lines of evidence that suggest a
fundamental role of proteoglycans in regulating the aqueous outflow
through the trabecular meshwork, we propose that these
proteoglycans are ideal candidate genes for glaucoma. POAG families
with a clear pattern of autosomal dominant inheritance will be part
of a study utilizing single stranded conformation analysis or
denaturing gradient gels to determine if a specific proteoglycan
may be the genetic defect in one or more of these families. It is
our view that POAG is a heterogeneous group of disorders, so that
each of these families may actually represent a defect in a
different proteoglycan or extracellular matrix component. The
ultimate goal of this grant proposal is to identify one or more
POAG genes. This may, in turn, lead to earlier detection and new
therapeutic approaches to this insidious cause of human blindness.