Department of Ophthalmology

Bärbel Rohrer, Ph.D.

Photograph of Dr. Rohrer
ABBREVIATED CV OF Dr. Rohrer

PEER-REVIEWED PUBLICATIONS 2007-2012

GRANT SUPPORT 2007-2012

LABORATORY PERSONNEL
 
Principal Investigator, Bärbel Rohrer, Ph.D.
 Complement activation in models of AMD
 
Res. Assist. Prof., Kusum Joseph, Ph.D.
  Staff Sci., Mausumi Bandyopadhyay, Ph.D.
  Postdoc. Sch., Gloriane Schnabolk, Ph.D.
  Postdoc. Sch., K. Kunchithapautham, Ph.D.
  Res. Tech I, Elizabeth O’Quinn, B.S.
  Graduate Student, Beth Coughlin, B.S.
  Graduate Student, Elisabeth Obert, B.S.
  Graduate Student, Alex Woodell, B.S.
  Visiting Scholar, Katherine Adams, B.S.
 Mitochondrial respiratory capacity in 
  photoreceptor degeneration
 
Visiting Assist. Prof., Chris. Lindsey, Ph.D.
                                                       Staff Sci., Mausumi Bandyopadhyay, Ph.D.
                                                       Postdoc. Sch., Nathan Perron, Ph.D.
                                                       Postdoc. Sch., Andrew Hunter, Ph.D.
                                                       Res. Tech I, Cecile Nasarre, Ph.D.
                                                       Graduate Student, Anthony Leonard, B.S.
 

SUMMARY OF LABORATORY RESEARCH
My lab is interested in investigating the mechanism of photoreceptor degeneration and neuroprotection.  The current projects in the lab were spun off from a study focused on identifying commonalities among photoreceptor dystrophies, in order to identify possibilities for common treatments.  Over the last ten years, the number of genes associated with photoreceptor dystrophies has almost doubled from ~100 to almost 200 genes (RetNet at http://www.retnet.org).  In addition, various environmental factors have been identified to trigger or augment the disease.  This heterogeneity has hampered the development of treatment strategies, and progress to develop treatments has been limited by the need to know the identities of potential rescue factors and their target genes in the photoreceptors.  Two key clusters included genes involved in energy metabolism and complement activation/neuroinflammation (e.g., Lohr et al., 2006; PMID: 16626700), which we chose to focus on.  Both projects are translational in that they start with a gene or a molecule, are examined in cell-based assays for mechanistic studies, and culminate in models for functional analyses.

Neuroinflammation and/or activation of the complement cascade have been implicated in a number of neurodegenerative diseases, including age-related macular degeneration (AMD).  A number of different models are currently being used to analyze various aspects of AMD.  The model of light-induced photoreceptor degeneration (LD) in albino mice is commonly used to investigate the role of oxidative stress; the model of argon-laser-induced choroidal neovascularization (CNV) is used to investigate angiogenesis.  We have used both models to further investigate the role of the alternative pathway of complement.  The alternative pathway is one of three entry points to activate the complement cascade, which is involved in inflammation, cell lysis and removal of debris via opsonization.  The alternative pathway inhibitor ‘complement factor H’ (CFH) has recently been identified to be associated with all forms of AMD, dry, wet and geographic atrophy.  In animals in which the alternative pathway of complement is eliminated by removing required activators of the cascade (CFB-/- or CFD-/-), both light-induced photoreceptor degeneration (Rohrer et al., 2007; PMID: 17962484) and CNV (Rohrer et al., 2009; PMID: 19264882) are significantly reduced.  These results confirm that pathological activation of the alternative pathway (AP) of complement is involved in both models.  In follow-up experiments we have shown that the alternative pathway is required, but not sufficient for disease (Rohrer et al., 2011; PMID: 21257205).  We are currently investigating how the classical and lectin pathways contribute to initiating the disease process.  To test whether exogenous inhibitors of the AP can be utilized to treat AMD, we have designed a targeted CFH, which utilizes a domain of the complement receptor 2 (CR2) that recognizes activated complement fused to the inhibitory domain of CFH (CR2-fH).  CR2-fH was found to block the progression of CNV as effectively as the gene knockout, by reducing VEGF expression and secretion by the RPE (Rohrer et al., 2009; PMID: 19264882).  In a cell-based model (RPE monolayers), we have shown that oxidative stress, one of the main environmental factors in AMD, down-regulates the levels of complement inhibitors of or at the cell surface, effectively reducing the cells ability to fight off complement attack (Thurman et al., 2009; PMID: 19386604).  As a consequence, sublytic complement activation results in VEGF (Kunchithapautham and Rohrer, 2011; PMID: 21566137) and MMP secretion (Bandyopadhyay and Rohrer, submitted), effectively generating a microenvironment amenable to pathology.

Cellular metabolism is highly indicative of cell survival, and early changes in cellular metabolism are predictive of future cell survival.  We have used a cytotoxicity model of retinal degeneration (Sharma and Rohrer, 2004; PMID: 15208318) and successfully used a high throughput, low information content viability assay to screen a high chemical diversity, 50,000 member compound library for protection of cell viability against the calcium and oxidant stresses known to cause death in this model.  The 12 leads identified in this screen were fed into our high information content secondary assays for mitochondrial function, confirming that 3 of the lead compounds increase mitochondrial capacity.  Our tertiary screen included promotion of cell survival in retinal organ cultures of rd1 mice (genotypic and phenotypic model for human RP), and confirmed efficacy for 2 out of the 3 compounds.  Finally, one of the compounds was tested in vivo and confirmed to be efficacious.  Follow-up studies for toxicology, pharmacology, etc. are planned. 

Top of Page

 
 
 

© Medical University of South Carolina | 171 Ashley Avenue, Charleston, SC 29425