Research

Mary Elizabeth Hartnett, MD, is the principal investigator of a National Institutes of Health-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.

Studying Aberrant Angiogenesis

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.

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) as intravitreal neovascularization (IVNV, Fig 1, showing a retina flat-mount stained with lectin to visualize the vasculature) 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.

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Fig 1

The 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.

To study mechanisms of invasive choroidal neovascularization in age-related macular degeneration (AMD), a co-culture model is used to understand causes of endothelial migration across the retinal pigment epithelium (Fig 2). This involves cell-cell models, animal models and study of human tissue. Relevant stresses associated with human AMD are used to test activation of signaling pathways compromising the integrity of the retinal pigment epithelial barrier and/or activating endothelial cells to migrate.

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Fig. 2

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.

Medical Student Research Program University of Utah

Dr. Hartnett’s lab mentors students who are participating in the summer Medical Student Research Program. This training program is funded by the National Institutes of Health and gives students the opportunity to work on their own projects in the Hartnett lab. Interested students may contact me.hartnett@hsc.utah.edu or maria.gomez@hsc.utah.edu.

Clinical Studies

1. Genetics of Pediatric Retinal Disorders

We are studying the blood of affected children along with their parents and siblings (both affected and unaffected) to determine both existing and new genetic variants associated with retinal diseases. The goal is to find targeted and safe therapies for retinal diseases.

2. Preclampsia Retinopathy of Prematurity

In order to study the relationship between preclampsia and ROP as well as the role of circulating anti-angiogenic factors, we propose to perform a chart review, looking at premature neonates (<31 weeks of gestation) and their mothers for the past 20 years and to correlate material clinical parameters to the presence and severity of ROP.

For a subset of the premature neonates, cord blood was collected as part of previous, IRB approved study. In this subset of patients, we propose to evaluate levels of soluble anti-angiogenic factors in the fetal cord blood and correlate these with presence and severity of ROP.

3. RAINBOW Study

This is a randomized, controlled study evaluating the efficacy and safety of Ranibizumab compared with laser therapy for the treatment of infants born prematurely with retinopathy of prematurity.

The purpose of this study is to determine if intravitreal ranibizumab is superior to laser ablation therapy in the treatment of retinopathy of prematurity (ROP). The study will assess the ability of these treatments to lead the regression of active ROP and prevent the development of ocular complications that are associated with poor visual outcome.

ROP1 – Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity to find a dose of intravitreal bevacizumab that is lower than currently used for severe ROP, is effective in this study, and can be tested in future larger studies.

4. Genetic Associations in Preterm Infants at Risk of Retinopathy of Prematurity

This proposal is for pilot data to support a large NIH-funded study and to initiate a biological bank from infants cared for at neonatal intensive care units at Primary Children’s Medical Center and University Hospital. In addition to a blood sample and cheek swab taken from the infants, we will also ask the parents and siblings of infants at risk of ROP to provide a blood sample for the study in order to aid the genetic analysis.

Our future goal is to include other neonatal units in the several centers throughout the United States and several world-wide to reduce heterogeneity from different populations.

5. Growth Factors in Vitreoretinal Diseases

The purpose of this study is to study the role of growth factors in the diseases of the retina and vitreous. To do this, we are creating a tissue bank of vitreous samples. Vitreous samples will be taken from participants of premature infants through adulthood. These samples are ones that would otherwise be discarded. Procedures to obtain these specimens are part of standard of care.

6. Spectral Domain Optical Coherence Tomography Imaging of Eyes: A Practical Diagnostic Tool and Methodology

The purpose of this study is to gather and evaluate high-depth resolution cross-sectional images of the eye obtained during spectral domain optical coherence tomography (SD-OCT) testing with a hand held adaptor on neonates with a variety of eye diseases or normal eyes. Spectral domain optical coherence tomography is a noninvasive technology. It relies on the analysis of light reflected from the back of the eye to create an image of the thickness of the retina and underlying tissues. OCT technology has been available for several years, but SD-OCT is the most advanced form commercially available. SD-OCT shows details that were once only seen on pathology.