CONTACT ADMINISTRATIVE SUPPORT
Learning, solving problems, unraveling new findings, studying ocular vascular function at a cellular level are what drive my research.
Appointments and Honors
Retina Research Foundation Alice R. McPherson Chair
Affiliate Appointments
Pharmacology
Carbone Comprehensive Cancer Center
Cardiovascular Research Center
Dr. Sheibani is a trainer in the Cellular and Molecular Biology, the Cellular and Molecular Pathology, and the Molecular and Environmental Toxicology Graduate Programs.
Research Interests
- Ocular vascular biology, diabetic retinopathy, retinopathy of prematurity, exudative age-related macular degeneration, drug development
- Metabolism and cellular function
The growth of new blood vessels from preexisting capillaries (angiogenesis) contributes to the pathogenesis of many diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, the major causes of blindness. Understanding the molecular and cellular mechanisms that regulate angiogenesis and, how their alterations contribute to growth of new blood vessels, has significant clinical impact. Our laboratory has demonstrated that thrombospondin-1 (TSP1), an endogenous inhibitor of angiogenesis, 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. This finding opens many new questions relating to the molecular and signaling mechanisms that mediate TSP1 activity. We have prepared cultures of vascular cells, including endothelial cells (EC), pericytes/smooth muscle cells, and astrocytes 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. Gene array analysis of retinal EC, with and without TSP1, has also identified a number of genes whose expression is differentially regulated. We are determining how alterations in the expression of these genes impact retinal EC phenotype and angiogenesis. Similar studies are being performed addressing the function of other angiogenesis related genes including CYP1B1, PECAM-1, endoglin, and members of bcl-2 family of proteins.
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 may 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, as well as nephropathies, are significantly exacerbated 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 and nephropathies. Future studies will focus on the contribution of TSP1 to altered cell adhesive interactions that results in loss of vascular cells, leakiness of blood vessels, hypervascularization of the retina and kidney, and loss of vision and renal function in diabetes. Similar studies are being performed with another endogenous inhibitor of angiogenesis, pigment epithelium derived factor (PEDF). The results of these studies will have great impact not only in understanding the mechanisms which normally keep ocular and renal vasculature in check but also aid in the advancement and design of new therapies to prevent loss of vision and kidney function in diabetes.
Research Highlights
For the first time in any research laboratory, Dr. Sheibani successfully isolated viable mouse retinal endothelial cells. A similar method has since been adopted to isolate other critical cell types of the mouse eye. These cells have been instrumental in enhancing our understanding of the many cell-autonomous activities impacted by the deletion of specific genes in these cells or their exposure to various pathological conditions. To date, the resulting cells have been provided to numerous investigators nationally and globally to foster ongoing research in the field. The publication highlighting this seminal work has received over 130 citations, and Professor Sheibani has presented at national and international meetings over 100+ times since publication.
Isolation and characterization of murine retinal endothelial cells
Dr. Sheibani has demonstrated the important role of thrombospondin-1, the first identified endogenous inhibitor of angiogenesis, in the development of retinal vasculature and how its expression plays a key role in ocular vascular homeostasis such that its reduced expression exacerbated the pathogenesis of diabetic retinopathy and choroidal neovascularization. He has also demonstrated mimetic peptides from thrombospondin-1 are efficacious in mitigation of choroidal neovascularization and progression of uveal melanoma tumor.
Dr. Sheibani elucidated the role of CYP1B1, known to be most frequently mutated in patients with primary congenital glaucoma. In his work, Dr. Sheibani discovered that CYP1B1 is important to oxidative homeostasis and the structural organization of collagen fibrils thereby affecting trabecular meshwork function. Furthermore, CYP1B1 was also found to modulate expression of a protein, periostin that is involved in trabecular meshwork development, and may prove to be an important biomarker for measuring treatment efficacy of glaucoma drug candidates in the future. He also showed a major impact for Cyp1b1 expression and regulation of angiogenesis. The work has resulted in 50+ citations and been presented 40+ times at national and international conferences.
Cyp1b1 mediates periostin regulation of trabecular meshwork development by suppression of oxidative stress
Dr. Sheibani was first to demonstrate the anti-angiogenic activity of vitamin D in a preclinical model of retinopathy of prematurity. He demonstrated that this activity requires the expression of vitamin D receptor. Using the various retinal vascular cell types generated, he demonstrated that vitamin D antiangiogenic activity is mediated through mitigation of angiogenic signaling in both endothelial cells and pericytes leading to stabilization of retinal vasculature.
Education
Postdoctoral Fellowship, 1992-96, Washington University School of Medicine, St. Louis, MO
Postdoctoral Fellowship 1989-92, University of Wisconsin, Madison, WI
PhD 1989, University of Nebraska Medical Center, Omaha, NE
MS 1985, University of New Hampshire, Durham, NH
BS 1982, Nasson College, Springvale, ME
Publications
Wang S, Wu Z, Sorenson CM, Lawler J, Sheibani N. Thrombospondin-1-deficient mice exhibit increased vascular density during retinal vascular development and are less sensitive to hyperoxia-mediated vessel obliteration. Dev Dyn. 2003;228(4):630-42. Epub 12/04. doi: 10.1002/dvdy.10412.
Wang S, Sorenson CM, Sheibani N. Lack of thrombospondin 1 and exacerbation of choroidal neovascularization. Arch Ophthalmol. 2012;130(5):615-20. Epub 2012/01/11. doi: archopthalmol.2011.1892 [pii]
10.1001/archopthalmol.2011.1892 [doi]. PubMed PMID: 22232368; PubMed Central PMCID: PMC3404202.
Wang S, Neekhra A, Albert DM, Sorenson CM, Sheibani N. Suppression of thrombospondin-1 expression during uveal melanoma progression and its potential therapeutic utility. Arch Ophthalmol. 2012;130(3):336-41. Epub 2012/03/14. doi: 130/3/336 [pii]
10.1001/archopthalmol.2011.1503 [doi]. PubMed PMID: 22411663; PubMed Central PMCID: PMC3381901.
Tang Y, Scheef EA, Wang S, Sorenson CM, Marcus CB, Jefcoate CR, et al. CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression. Blood. 2009;113(3):744-54. Epub 2008/11/14. doi: 10.1182/blood-2008-03-145219. PubMed Central PMCID: PMCPMC2628380.
Palenski TL, Gurel Z, Sorenson CM, Hankenson KD, Sheibani N. Cyp1B1 expression promotes angiogenesis by suppressing NF-κB activity. Am J Physiol Cell Physiol. 2013;305(11):C1170-84. doi: 10.1152/ajpcell.00139.2013.
Palenski TL, Sorenson CM, Jefcoate CR, Sheibani N. Lack of Cyp1b1 promotes the proliferative and migratory phenotype of perivascular supporting cells. Lab Invest. 2013;93(6):646-62. Epub 2013/04/10. doi: 10.1038/labinvest.2013.55. PubMed Central PMCID: PMCPMC3791926.
Albert DM, Scheef EA, Wang S, Mehraein F, Darjatmoko SR, Sorenson CM, et al. Calcitriol is a potent inhibitor of retinal neovascularization. Invest Ophthalmol Vis Sci. 2007;48(5):2327-34. PubMed PMID: 17460298.
Jamali N, Wang S, Darjatmoko SR, Sorenson CM, Sheibani N. Vitamin D receptor expression is essential during retinal vascular development and attenuation of neovascularization by 1, 25(OH)2D3. PLoS One. 2017;12(12):e0190131. Epub 2017/12/23. doi: 10.1371/journal.pone.0190131. PubMed PMID: 29104816.
Jamali N, Song Y-S, Sorenson CM, Sheibani N. 1,25(OH)2D3 regulates the proangiogenic activity of pericyte through VDR‐mediated modulation of VEGF production and signaling of VEGF and PDGF receptors. FASEB BioAvances. 2019;1:415-34. doi: 10.1096/fba.2018-00067.