The Hartnett Laboratory

chart of visual response

Mary Elizabeth Hartnett, MD, is Principal Investigator of an NIH-funded laboratory that studies mechanisms of normal and aberrant angiogenesis, particularly related to diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration. The mission of the laboratory is to understand what causes blood vessels to grow outside their normal tissue compartments and into other areas of the eye where they cause damage.  Rather than inhibit or destroy abnormal vessels, the goal is to understand what simulates endothelial cells of blood vessels to become activated to migrate and proliferate aberrantly, and once this is known, to then restore or contain blood vessel support to normal ocular compartments.avasular retina

Dr. Hartnett and her team of researchers are investigating multiple causes of aberrant angiogenesis. One is retinal avascularity, or a lack of blood vessel support in areas of the inner retina that leads to retinal hypoxia, which stimulates aberrant growth of blood vessels. One important observation the Hartnett lab made was that overactivation of the signaling pathway of vascular endothelial growth factor (VEGF) actually contributes to retinal avascularity by disordering the growth of endothelial cells, causing them to grow into the gel of the eye (vitreous) rather than normally into the retina. Another cause of abnormal angiogenesis is the generation of damaging reactive oxygen species, which can lead to loss of the integrity of  the cell junctions, which are important in maintaining normal compartmentalization of tissues.

The Hartnett lab has made important observations regarding the mechanisms whereby the GTPase, Rac1, is activated in choroidal endothelial cells to cause endothelial cell migration across the RPE.  Dr. Hartnett has found that several proteins interact with the VEGF receptor to overactivate the receptor and effectors that are downstream of this activation. Some of the effectors include Rac1, which causes migration of the choroidal endothelial cells to form choroidal neovascularization such as what occurs in neovascular AMD, and STAT3 in endothelial cells, which leads to aberrant intravitreal angiogenesis. 

VEGFThe Hartnett lab uses transgenic mouse models or models in other species that better represent human diseases. In species in which transgenic modeling is difficult, Dr. Hartnett has used gene therapy to knockdown proteins in specific cells in the retina. These techniques have been important in understanding cell-specific roles of proteins within the retina and also in understanding the interactions that different cells within the retina have on one another to lead to pathology as opposed to what is learned from solo cell experiments.

The Hartnett Laboratory uses a number of imaging methods such as the Micron IV in combination with fluorescein angiography and spectral domain optical coherence tomography to analyze retinal structure and to localize laser injury simultaneously to regions within the retina that have been transduced by gene therapy. These methods, in conjunction with cell coculture techniques, help the lab work out mechanisms of disease with the hopes of finding cures for blinding eye diseases.

The laboratory is vibrant and includes several laboratory members:  Haibo Wang, MD, PhD is the research assistant professor working mainly on the molecular mechanisms involved in endothelial cell migration and junctional integrity of the retinal pigment epithelium. Deeksha Gambhir, PhD is a post-doctoral student studying the role of GTPases in restricting choroidal neovascularization from the sensory retina. Lori Fotheringham is the chief animal and laboratory technician overseeing the day to day running of the laboratory.

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Education: BS, Biology, Rensselaer Polytechnic Institute, Troy, NY
Medical School: Albany Medical College, Albany, NY
Internship: Internal Medicine, University Hospitals of Cleveland/Case Western Reserve, Cleveland, OH
Residency: Ophthalmology, University Hospitals of Cleveland/Case Western Reserve Cleveland, OH
Fellowships: Adult and Pediatric Vitreoretinal Diseases and Surgery, Schepens Retina Associates, Massachusetts Eye Research Institute, Harvard Medical School, Boston, MA

Certifications: Ophthalmology - Board Certified (1989)

Academic Appointments: Professor, Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine

Recent Publications:

1.  Wang, H, Zhang SX, Hartnett ME.  (2013). Signaling pathways triggered by oxidative stress that mediate features of severe retinopathy of prematurity.  JAMA Ophthalmol, 131(1), 80-5.

2.  McCloskey M, Wang H, Jiang Y, Smith GW, Strange J, Hartnett ME. (2013). Anti-VEGF antibody leads to later atypical intravitreous neovascularization and activation of angiogenic pathways in a rat model of ROP. Invest Ophthalmol Vis Sci, 54(3): 2020-6

3.  Hartnett ME, Owen L. (2013). Soluble mediators of diabetic macular edema:  the diagnostic role of aqueous VEGF and cytokine levels in diabetic macular edema. Curr Diab Rep. 13(4): 476-80.

4.  Wittchen ES, Nishimura E, McCloskey M, Wang H, Quilliam LA, Chrzanowska-Wodnicka M, and Hartnett ME. (2013). Rap1 GTPase activation and barrier enhancement in RPE inhibits choroidal neovascularization in vivo. PLOS ONE.

5.  Wang H, Smith GW,Yang Z, Jiang Y, McCloskey M, Greenberg K, Geisen P, Culp WD, Flannery J, Kafri T, Hammond S, Hartnett ME. (2013). Short hairpin RNA mediated knockdown of VEGFA in Müller cells reduces intravitreal neovascularization in a rat model of ROP. American Journal of Pathology.

6.  Wang H, Jiang Y, Shi D, Quilliam LA, Chrzanowska-Wodnicka M, Wittchen ES, Li DY, Hartnett ME. (2014). Activiation of Rap1 inhibits NADPH oxidase-dependent ROS generation in retinal pigment epithelium and reduces choroidal neovascularization. FASEB J, 28(1):265-74. Epub 2013, Sept.

7.  Wang H, Yang Z, Jiang Y, Hartnett, ME. (2014). Endothelial NADPH oxidase 4 mediates vascular endothelial growth factor receptor 2-induced intravitreal neovascularization in a rat model of retinopathy of prematurity. Mol Vis, 20, 231-xxx.

8.  Jiang Y, Wang H, Culp D, Yang Z, Fotheringham L, Flannery J, Hammond S, Kafri T, Hartnett ME. (2014). Targeting Muller cell-derived VEGF 164 to reduce intravitreal neovascularization in the rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci, 55(2), 824-31.

9.  Wang H, Yang Z, Jiang Y, Flannery J, Hammond S, Kafri T, Vemuri SK, Joned B, Hartnett ME. (2014). Quantitative analyses of retinal vascular area and density after different methods to reduce VEGF in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci, 55(2), 737-44.

10. Yang Z, Wang H, Jiang Y, Hartnett ME. (2014). VEGFA Activates Erythropoietin Receptor and Enhances VEGFR2-mediated Pathological Angiogenesis. Am J Pathol, 184(4), 1230-9.

11. Hartnett ME. (2014). Pathophysiology and Mechanisms of Severe Retinopathy of Prematurity. Ophthalmology. Oct; [Epub ahead of print].

12. Hartnett ME. (2014). Vascular Endothelial Growth Factor Antagonist Therapy for Retinopathy of Prematurity. Clin Perinatol. Dec;41(4):925-943.