Text Size Normal Text Sizing Button Medium Text Sizing Button Large Text Sizing Button Text Contrast Normal Contrast Button Reverse Contrast Button Switch to Spanish Language Press Room Contact Us Sitemap Sign In Register
Link to Homepage About BrightFocus
BrightFocus
Donate Now Get Involved  
Alzheimer's Disease Research Macular Degeneration Research National Glaucoma Research


Sign up for Email Notifications
If you would like to be notified when funding or meeting opportunities are announced please click on the link below.

Sign up for new announcements.

Please add ResearchGrants@BrightFocus.org to your institution’s white list to insure that the notification is not blocked by your organization’s SPAM filters.

This email list is not sold or distributed, and serves only as an annual reminder of the availability of research support through the BrightFocus Foundation (www.brightfocus.org). Please follow instructions on the notification emails for removal requests.

 
 
BrightFocus Research Grants Funding
Grant Funding for Alzheimer's Research
Grant Funding for Macular Degeneration Research
Grant Funding for Glaucoma Research
 

 

National Glaucoma Research
Completed Award

Raquel Lieberman

Raquel Lieberman, Ph.D.

Georgia Institute of Technology
Atlanta, GA

Title: Development of pharmacological chaperone therapy for inherited primary and juvenile open angle glaucoma
Non-Technical Title: The search for a new therapy for inherited glaucoma

Acknowledgements: Recipient of the Thomas R. Lee award for National Glaucoma Research
Duration: April 1, 2008 - March 31, 2011
Award Type: Standard
Award Amount: $100,000

Summary:

The researchers' aim is to develop a new therapy for inherited glaucoma, which in many cases is caused by mutations in a protein called myocilin.

Details:

The researchers' aim is to develop a new therapy for inherited glaucoma, which in many cases is caused by mutations in a protein called myocilin. Myocilin forms part of the trabecular extracellular matrix (TEM) in the eye and is important in regulating eye pressure. When the TEM doesn't function correctly, eye pressure increases, leading to retinal degeneration and vision loss. Human trabecular meshwork (HTM) cells, which produce the matrix, recognize mutations in myocilin and prevent mutant myocilin from being secreted to the TEM. Instead, mutant myocilin remains in the interior of HTM cells, causing the HTM cells to die. This disrupts the TEM, causing increased eye pressure and eventually glaucoma. The team hopes to discover a drug molecule that interacts with mutant myocilin inside the HTM cells to restore secretion of myocilin to the TEM. This could prevent the mutant protein from accumulating in the HTM cells and keep these cells alive. In addition, the TEM could be restored and better able to control eye pressure. This should slow the retinal degeneration associated with glaucoma. The researchers seek to better understand the molecular structure of myocilin, and then to identify and test drug candidates that bind to the myocilin.

Publications:

Burns, J. N., Orwig, S. D., Harris, J. L., Watkins, J. D., Vollrath, D. and Lieberman, R. L. (2010) Rescue of glaucoma-causing mutant myocilin thermal stability by chemical chaperones. ACS Chemical Biology, ASAP 3/24/10. (DOI: 10.1021/cb900282e) PubMed Icon Google Scholar Icon

The study reports the first high yield expression and purification of OLF, including a new assay to compare stability, and demonstration that 4 disease-causing mutants can be stabilized to near wild-type levels by small molecules. This publication was just released.

Orwig, S. D. and Lieberman, R. L. Biophysical characterization of the olfactomedin domain of myocilin, an extracellular matrix implicated in the inherited form of glaucoma. PLoS ONE, 6(1): e16347, 2011. (doi:10.1371/journal.pone.0016347) PubMed Icon Google Scholar Icon

Orwig, S. D., Perry, C. W., Kim, L. Y., Turnage, K. C., Zhang, R., Vollrath, D., Schmidt-Krey, I., and Lieberman, R. L. Amyloid Fibril Formation by the Glaucoma-Associated Olfactomedin Domain of Myocilin. J Mol Biol. 2011 Dec 13. [Epub ahead of print] PubMed Icon Google Scholar Icon

Progress Updates:

Dr. Raquel Lieberman and collaborators studied the structure and stability of myocilin, the protein most strongly linked to both adult-onset and juvenile inherited Primary Open Angle Glaucoma (POAG). Myocilin protein forms part of a matrix in the eye that is important in regulating eye pressure. Human trabecular meshwork (HTM) cells, which generate the matrix components, recognize mutant myocilin proteins and prevent them from being secreted to the matrix. However, the mutant proteins remain inside HTM cells, causing these cells to die. This results in a disrupted matrix and increased eye pressure, eventually leading to glaucoma.

To understand how mutant myocilin can cause glaucoma, Dr. Lieberman and collaborators first found a way to express and purify large quantities of normal and selected mutant versions of this protein. Next, these researchers discovered the conditions for "crystallization" of these purified proteins into a form that could be used to determine their structures. Now that they have the myocilin crystals, no doubt they will soon determine its three dimensional structure. Finally, they developed a sensitive, high-throughput assay to determine the stability of the different forms of myocilin. Dr. Lieberman will use the information and techniques generated through this award to search for a new glaucoma drug that may restore the secretion of myocilin and save the HTM cells from dying.