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THROMBOSPONDINS in Ocular Vascular Homeostasis
The growth of new blood vessels (angiogenesis) contributes to the pathogenesis of many diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, the major causes of vision loss worldwide. Understanding the molecular and cellular mechanisms that regulate angiogenesis will aid in the development of angioinhibitory agents for treatment of these diseases. Our laboratory has demonstrated that thrombospondin-1 (TSP1) is an important modulator of retinal vascular homeostasis. Mice deficient in TSP1 fail to undergo appropriate vascular pruning and remodeling during postnatal vascularization of the retina; as a result, they exhibit increased retinal vascular density. We have also shown a TSP1 memetic peptide is efficacious in attenuation of angiogenesis in various eye diseases. This finding opens many new questions relating to the molecular and signaling mechanisms that mediate TSP1 activity. We have recently prepared a targeted transgenic line of TSP1 to study cell autonomous function of TSP1 in vivo. We have also prepared cultures of vascular cells, including endothelial cells (EC), pericytes/smooth muscle cells, and astrocytes as well as choroidal EC and PC and RPE cells from TSP1-/- and wild type mice. A goal of our lab is to determine the role TSP1 plays in coordinating the interactions among these cells during postnatal vascularization of the retina and choroid. Gene expression analysis of vascular cells, with and without TSP1, has also identified several genes whose expression is differentially regulated. Determining how alterations in the expression of these genes impact retinal vascular and inflammatory cell’s phenotype during angiogenesis and inflammation will aid in the development of new therapeutics.
CYP1B1 and Modulation of Ocular Redox Homeostasis
Cytochrome P450 1B1 is a member of the cytochrome P450 family of enzymes whose mutations contribute to highest percentage of congenital glaucoma in humans. How mutations in CYP1B1 cause abnormal development of the eye’s anterior chamber and the resulting glaucoma remains largely unknown. The cells of the trabecular meshwork and Schlemm’s canal share many characteristics of vascular cells. Expressions of CYPs in vascular cells are proposed to be involved in the development and progression of many vascular diseases. We previously found that the normal postnatal retinal vascularization and its neovascularization during oxygen-induced ischemic retinopathy are attenuated in CYP1b1 null mice. Furthermore, vascular cells prepared from these mice exhibit migratory and adhesive defects and fail to form capillary networks in Matrigel. However, culturing of the CYP1b1-/- cells under low oxygen tension or in the presence of N-acetylcysteine (NAC) restores their normal migratory and morphogenic properties. Furthermore, administration NAC is sufficient to prevent the dysgenesis of TM in Cyp1b1-/- mice. Thus, these results indicate that expression of CYP1B1 may be essential for maintaining redox hemostasis with important role in ocular vascular homeostasis and tissue regeneration. We recently have generated a floxed transgenic line of Cyp1b1 to further delineate the cell autonomous function of Cyp1b1 in vivo. Our current efforts are to establish how reduced levels of CYP1B1 expression/activity contribute to increased oxidative stress in the endothelium and mitigation of angiogenesis and impact the dysgenesis of conventional outflow pathways resulting in congenital glaucoma.
Metabolic Stress and DIABETIC RETINOPATHY
In separate studies, we have discovered that TSP1 is present at a significantly high level in the vitreous and aqueous humors of normal eyes, but its level is decreased at these sites during diabetes. Therefore, changes in TSP1 levels during diabetes could contribute to the development and progression of diabetic retinopathy. Our current studies indicate that in the absence of TSP1, the development and progression of retinopathies is significantly expedited in a novel diabetic model developed in our laboratory. Utilizing these mice, we are studying how lack of TSP1 exacerbates the development and progression of early diabetic retinopathies. Our studies are focusing on the contribution of TSP1 to altered cell adhesive interactions and metabolic changes that results in loss of vascular cells, leakiness of blood vessels, hypervascularization of the retina, and loss of vision in diabetes. Our most recent focus has been on selective sensitivity of retinal neurovascular cells to hyperglycemic conditions and the role various metabolic pathways play in these selective sensitivities to diabetes conditions. The results of these studies will have great impact not only in understanding the mechanisms which normally keep ocular vascularization in check but also aid in the advancement and design of new therapies to prevent loss of vision in diabetes as well as other eye diseases.
Caffeine, Adenosine Receptors, and EXUDATIVE AMD
Adenosine receptors are widely expressed in various tissues including the retina and brain. The antagonism of these receptors has shown beneficial effects in neurodegenerative diseases such as Parkinson and Alzheimer. Recently, the antagonism of these receptors by caffeine is shown to protect preterm infants from ischemic retinopathy and retinal neovascularization. Caffeine is a widely consumed adenosine receptor antagonist and has established roles in the treatment of neonatal sleep apnea, acute migraine, and post lumbar puncture headache. Both the adenosine receptor antagonist (caffeine) and its agonist (adenosine) influence inflammation and vascular cell function in the retina. Adenosine accrues with cell stress, damage, and inflammation. Its receptor engagement restores oxygen balance while regulating inflammation and angiogenesis. The type of injury inflicted, mode of drug administration, and cells involved can influence the outcome in a context dependent manner. Little is known about the role adenosine and its receptors play in the development and progression of CNV. We recently showed caffeine is efficacious in mitigating CNV. However, the role adenosine receptors play in a preclinical murine model exudative AMD and the identity of mechanisms of adenosine receptor-based therapies need investigation. We believe targeting adenosine receptors may provide alternative therapy for nAMD patients that do not respond to anti-VEGF.
Thrombospondin-1, Modulation of Choroidal Mast Cells, and ATROPHIC/DRY AMD
Recent studies have demonstrated a strong association between the presence of activated mast cells (MC), loss of retinal pigment epithelium (RPE) cells, and pathogenesis of dry AMD. Unfortunately, the underlying molecular mechanisms remain unclear. Sodium iodate (NaIO3) induced loss of RPE cells and degeneration of photoreceptor cells closely mimics the events noted in dry AMD and geographic atrophy (GA). Although NaIO3 is shown to induce death of RPE cells, its contribution to MC activation in this model is unknown. In addition, it is unclear what normally keeps MC activation in check and whether MC activation is essential in pathogenesis of dry AMD. Although thrombospondin-1 (TSP1) is a well-known endogenous inhibitor of inflammation and angiogenesis, its impact during the pathogenesis of dry AMD remains unknown. We propose that the TSP1 expression is essential for tempering MC activation and keeps RPE cell function in check. When TSP1 expression decreases in AMD patients it could facilitate MC activation, RPE cell dysfunction, and progression of dry AMD. We are investigating the role of TSP1 in regulation of angiogenesis and inflammation and its cell autonomous function in various ocular cells including choroidal vascular cells, MC, and RPE cells in vitro. We have also generated a targeted line of TSP1 transgenic (Thbs1flox/flox) mice, which will allow us to interrogate these mechanisms in vivo.
Interested in our research? Consider joining the Sheibani Lab Team.
The Sheibani Lab is always eager to hear from interested graduate students and prospective post-doctorate fellows. If you would like to study ocular vascular function, inflammation at a cellular level, and play an integral role in identifying new therapeutic targets for neovascular eye diseases, we’d love to hear from you. Please send a CV or statement of interest to email@example.com. Available positions are based on the funding status of new and ongoing projects. Projects will be posted here, so check back soon!