McGahan, Christine, PhD
Professor of Pharmacology and
Department
Head
PhD: 1980, Pharmacology, Mount Sinai School of Medicine, City
University of New York. Mentor, Dr. Peter Bentley
Post-doctoral: 1981-2, Harkness Eye Institute, Columbia University
College of Physicians and Surgeons. Mentor, Dr. Laszlo Bito
E-mail: chris_mcgahan@ncsu.edu
Current Positions:
Member, National Advisory Eye Council, 2007-2011
Secretary, International Society for Eye Research, 2008-2011 (elected position)
Grant Support:
NIH:
Principal Investigator:
1983-1986: NIH New Investigator Award EY-04900-01,2,3. Trace element dynamics in the vertebrate eye. (1/83-3/86; $149,730)
1986-1989: NIH grant EY-04900-04,5,6. Trace element dynamics in the vertebrate eye. (4/86-6/89; $348,226)
1989-1992: NIH grant EY-04900-7,8,9. Trace element dynamics in the vertebrate eye. (7/89-6/92; $467,074)
1992-1997: NIH grant EY-04900-10-14. Trace element dynamics in the vertebrate eye. (7/92-6/97; $1,031,541) Dr. M. Nasisse, Co-investigator.
1997-2001: NIH grant EY-04900-15-18. Trace element dynamics in the vertebrate eye. (7/97-6/01; $1,195,036)
2001-2006: NIH grant EY-04900-19-23. Trace element dynamics in the vertebrate eye. (7/01-6/06; $1,648,125)
2006-2011: NIH grant EY-04900-24-28. Trace element dynamics in the vertebrate eye (7/06-6/11; $1,272,670)
Research Areas:
Regulation of Fe metabolism in the eye, the involvement of Fe in cataract formation, mechanisms underlying post-surgical regrowth of lens tissue, uveitis, retinal physiology & pathology.
Current Research:
All projects in this lab are based on studies of iron metabolism in the eye.
Overall Hypothesis:
Alterations in cellular iron metabolism and storage in the lens and retinal pigmented epithelial cells result in significant changes in the size of the labile iron pool with concomitant physiological changes in glutamate and glutathione production and secretion, the activity of HIF-, the potential for pathophysioligcal changes and decreased ability to resist oxidative stress.
Lens Project:
Cataract is a significant health and economic problem worldwide. In the United States and in other developed countries this is primarily an economic issue since surgery is readily available and is such an effective treatment. However, this is a multi-billion dollar expense, making up 12% of the entire Medicare Budget. In addition, there are some significant side-effects to cataract surgery. In developing countries, cataracts are the leading cause of blindness. Oxidative damage has been implicated as a causative factor in cataract formation and iron-catalyzed free radical reactions are responsible for virtually all oxidative tissue damage. Significantly, the level of iron is increased in older and in cataractous lenses. In addition to catalyzing oxidative damage and serving as an essential component of key enzymes, new roles for iron in cellular physiology are emerging. For example, we have made the novel observation that iron regulates glutamate production and the concentration of the powerful intracellular reducing agent, glutathione (GSH). Furthermore, others have shown that iron regulates the availability of the transcription factor, hypoxia inducible factor (HIF-1α). HIF-1α exerts significant effects on iron metabolism by controlling transcription of key proteins such as heme oxygenase, transferrin, transferrin receptor and ceruloplasmin (Cp). All cells carefully control iron uptake, utilization and storage. Most intracellular iron is safely stored in ferritin or incorporated into iron-dependent enzymes. However, there is a pool of chelatable iron in cells that is called the labile iron pool (LIP) that is thought to be a central transit pool from which iron is moved to sites of storage, utilization or removal from the cells and as such has been proposed to regulate iron-dependent intracellular reactions. The LIP is the likely source of iron for catalyzing free radical reactions. Little is known about regulation of the LIP, but it is possible to experimentally alter its size which we hypothesize will cause significant downstream effects (Fig. 1) the ubiquitous iron storage protein, ferritin, safely sequesters large quantities of iron, thus limiting the size of the LIP. Ferritin is made up of 24 subunits of two types, heavy (H) and light (L) that are present in tissue-specific ratios. Alteration of this ratio changes iron storage and the size of the LIP. Other factors which alter the size of the LIP include iron overload, iron depletion and chelation and treatment with Cp and transferrin.
Our data have shown that:
- H- and L-chain ferritin composition in LEC changes with age and the structure of both chains is strikingly different from ferritin in the fiber mass.
- Altering the H:L ratio by overexpression of each chain or siRNA treatment changes iron metabolism and glutamate production.
- Iron controls the production of glutamate and the activity of the glutamate/cystine antiporter (Xc-). Increased glutamate antiporter activity increases cystine uptake.
- Cp increases the size of the LIP and increases glutamate secretion.
- HIF-1α and one of its targets, vascular endothelial growth factor (VEGF), are present in LEC and their availability is regulated by iron.
- Iron chelation and inhibition of aconitase-driven glutamate production decreases cystine uptake and GSH levels.
Retina Project:
Dysregulation of iron metabolism has been strongly implicated in the progression of both neurological and retinal diseases, but little is known about the specific metabolic disturbances which underlie these processes. Iron is central to cellular metabolism and recent findings in our laboratory indicate new roles for this trace element which are critically relevant to retinal function (see Fig. 1). We have demonstrated that iron regulates glutamate production and secretion in a number of different cell types including retinal pigment epithelial cells (RPE). This is important to the retina for two reasons, first glutamate is an important neurotransmitter which can be excitotoxic and second, glutamate secretion by an antiporter provides cysteine for intracellular production of the powerful antioxidant, glutathione (GSH). Others have found that iron regulates the activity of the transcription factor, hypoxia inducible factor-1 (HIF-1). More than 60 proteins are regulated by HIF-1. We have convincing preliminary data indicating that iron regulates HIF-1, the downstream production of vascular endothelial growth factor (VEGF) and other iron regulatory proteins in RPE cells.
Collaborations:
We have collaborated with Dr. Fleisher on his studies of the influence of cytokines on the uveitic response. Please see his website for more information.
We have collaborated with Dr. Davidson using his model for after-cataract formation in order to determine the mechanisms underlying this pathology in order to develop a means for preventing its occurrence. Please see his website for more information.
We are beginning a new collaboration concerning the involvement of iron in ocular inflamation in equine recurrent uveitis.
Representative Publications:
Goralska, M., R. Dackor, B.L. Holley, M.C. McGahan. 2003. Alpha lipoic acid changes Fe uptake and storage in lens epithelial cells. Exp. Eye Res. 76(2):241-8.
Harned, J., A.M. Grimes and M.C. McGahan. 2003. The effect of UVB irradiation on ferritin subunit synthesis, ferritin assembly and Fe metabolism in cultured canine lens epithelial cells. Photochem. Photobiol. 77:440-445.
Goralska, M., B.L. Holley and M.C.McGahan. 2003. Identification of a mechanism by which lens epithelial cells limit accumulation of overexpressed H-chain ferritin. J. Biol. Chem. 278:42920-42926.
McGahan, M.C., J. Harned, M. Mukunnemkeril, M. Goralska, L.N. Fleisher, J. Ferrell. 2005. Iron alters glutamate secretion by regulating cytosolic aconitase activity. Am. J. Physiol. 288:C1117-C1124.
Goralska, M., S. Nagar, L.N. Fleisher and M.C. McGahan. 2005. Differential degradation of ferritin H- and L- chains: accumulation of L-chain rich ferritin in lens epithelial cells. Invest. Ophthalmol. Vis. Sci. 46: 3521-3529. Cover article.
Harned, J., L.N. Fleisher and M.C. McGahan. 2006. Lens epithelial cells synthesize and secrete ceruloplasmin: effects of ceruloplasmin and transferrin on iron efflux and intracellular iron dynamics. Exp. Eye Res. 83(4):721-7. Epub 2006 Jun 23.
Goralska, M., L.N. Fleisher, M.C. McGahan. 2007. Ferritin H- and L-chains in fiber cells from canine and human lenses of different ages. Invest. Ophthalmol. Vis. Sci. 48(9):3968-75
Lall, M., J. Ferrell, S. Nagar, M.C. McGahan. 2008. Iron regulates L-cystine uptake and glutathione levels in lens epithelial and retinal pigment epithelial cells by its effect on cytosolic aconitase. Invest. Opthalmol. Vis. Sci. 49:310-319 (Cover article)
Goralska, M., S. Nagar, C.M. Colitz, L.N. Fleisher, M.C. McGahan. 2009. Changes in ferritin H- and L-chains in canine lenses with age-related nuclear cataract. Invest. Ophthalmol. Vis. Sci. 50:305-310 (Cover article)
M. Goralska, J. Ferrell, J. Harned, M. Lall, S. Nagar, L.N. Fleisher, M.C. McGahan. Iron metabolism in the eye: A review. Experimental Eye Research 88 (2009) 204-215.
Presentations at meetings:
McGahan, M.C., L.N. Fleisher and M. Goralska. 2003. Iron influences NADPH production by both isocitrate dehydrogenase and glucose-6-phosphate dehydrogenase. Invest. Ophthalmol. Vis. Sci. (Suppl). 44:1244
Goralska, M. and M.C. McGahan. 2003. Does ferritin secreted by canine lens epithelial cells play a role in maintaining cellular iron homeostasis? Invest. Ophthalmol. Vis. Sci. (Suppl.) 44:1243
McGahan, M.C., J. Harned, M.Mukunnemkeril, M. Goralska, L.N. Fleisher, J. Ferrell. 2004. Glutamate secretion by retinal pigment epithelial cells is regulated by iron. Invest. Ophthalmol. Vis. Sci. (Suppl.) 45:641
McGahan, M.C., J. Harned, L.N. Fleisher. 2005. Ceruloplasmin is made and secreted by lens epithelial cells and alters iron availability. Invest. Ophthalmol. Vis. Sci. (Suppl.) Abstract #3853
Mukunnemkeril, M., J. Ferrell, M.C. McGahan. 2005. Evidence for an iron regulated glutamatergic system in cultured lens epithelial cells. Invest. Ophthalmol. Vis. Sci. (Suppl.) Abstract #1900
Goralska, M., M.C. McGahan. 2006. Properties of ferritin in the lens fiber mass changes with age. Invest. Ophthalmol. Vis. Sci. (Suppl.) Abstract #2534
Nagar, S., M. Mukunnemkeril, L.N. Fleisher, M.C. McGahan. 2006. A glutamate/cystine antiporter is present in the lens and its activity is regulated by iron. Invest. Ophthalmol. Vis. Sci. (Suppl.). Abstract #4097
McGahan, M.C., M. Mukunnemkeril, S. Nagar, J. Harned, L.N. Fleisher, J. Ferrell. 2006. Iron regulation of glutamate secretion, glutathione synthesis and the activity of hypoxia-inducible factor in the lens and RPE. Invited paper, International Congress of Eye Research, Buenos Aires, Argentina, November 2006.
Goralska, M., M.C. McGahan. 2006. Modification of ferritin chains in dog and human lens fiber cells. Presented at the XVII International Congress of Eye Research, Buenos Aires, Argentina, Nov. 2006
McGahan, M.C., J. Ferrell, M. Mukunnemkeril, L.N. Fleisher, S. Nagar, M. Goralska, J. Harned.
2007. Alteration of ferritin subunit composition changes iron metabolism in lens epithelial cells with downstream effects on glutathione levels and vascular endothelial growth factor secretion. Invest. Ophthalmol. Vis. Sci. (Suppl.) Abstract #2436
McGahan, M.C., J. Ferrell, L.N. Fleisher, S. Nagar, M.M. Lall, J. Harned. 2008. Proteins integral to iron metabolism are regulated by hypoxia-inducible factor-1 in retinal pigmented epithelial cells. Invest. Ophthalmol. Vis. Sci. (Suppl.) Abstract #
Goralska, M., S. Nagar, C. Colitz, L.N. Fleisher, M.C. McGahan. 2008. Characteristics of ferritin H-and L-chains in canine lenses with age-related nuclear cataracts. Presented at the XVIII International Congress of Eye Research, Beijing, China, Sept. 2008