Apoptosis and cell death; Inherited Metabolic Disorders; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Regulation of metabolism; Transgenic organisms; Vision science
Our lab is focused on studies of retinal degenerations caused by metabolic defects, particularly dyslipidemias involving defective cholesterol metabolism (e.g., Smith-Lemli-Opitz syndrome), using pharmacological and transgenic animal models. Current studies are focused on the role of lipid and protein oxidation in the underlying mechanisms of photoreceptor cell death in such retinal degenerations, using a combination of genomic, proteomic, and lipidomic approaches.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular genetics; Stem Cells; Transcription and Translation; Transgenic organisms; Vision science
We are interested in the fundamental mechanisms underlying the shift of cellular states from progenitors to fully functional mature cell types along individual cell lineages during development. We address this issue by studying cell fate specification and differentiation in the developing neural retina. Our efforts are on identifying key regulators, uncovering their roles in individual lineages, and understanding how they carry out these roles. Current projects are emphasized on how transcription factors influence the epigenetic landscape along the retinal ganglion cell lineage. We conduct our research using a combinatorial approach encompassing genetics, molecular biology, genomics, single cell analysis and bioinformatics.
Cornea & External Disease; Ophthalmology; Vision science
As a specialist in cornea and external diseases of the eye, I treat a wide range of eye problems and perform a variety of surgical procedures including corneal transplantation, cataract surgery, conjunctival tumor surgery, and transplantation of the artificial cornea when standard corneal transplantation has failed. One of the most common reasons for corneal transplantation is corneal edema. Edema of the cornea develops from loss of corneal endothelial cells and causes irreversible vision loss in thousands of people yearly. Beyond surgical transplantation of the endothelial cell layer with human donor corneal tissue, no vision-restoring treatments are available. My research investigates the physiology regulating corneal hydration to advance future treatments for these patients. There are two main projects in my lab. The first looks at characterizing changes occurring in endothelial cell monolayer intercellular junctions and passive paracellular transport properties at low and high cell densities. Clinically, patients do not experience deterioration in vision or corneal edema until very low densities. The molecular basis for this observation is unknown. This project investigates changes in the apical junctional complex and monolayer permeability of the endothelium. The second project examines the mechanisms and regulation of active water transport out of the cornea. Using Ussing chamber physiology techniques, my lab is isolating the contributions and regulation of various ionic currents across the corneal endothelium with a focus on the contributions of potassium channels, bicarbonate and carbonic anhydrase inhibitors.
Ophthalmology; Retina; Pediatric Ophthalmology; Pathophysiology; Vision science
Dr. Reynolds has various research interests in pediatric ophthalmology, but his main niche is retinopathy of prematurity. ROP is a disease of the developing immature retinal vasculature, modulated by hyperoxia/hypoxia micro environments in the retina, which can lead to neovascularization, scarring, and potential blindness. Dr. Reynolds is a recognized expert in the field and is the author of many peer reviewed articles and several invited review chapters. His NIH funding has been nearly continuous while at U.B. while participating in several multi-center clinical trials in ROP as center P.I. and project director. Dr. Reynolds was the center P.I. at U.B. for the first large treatment trial for ROP, CRYO-ROP. This trial established the first known effective treatment for this high socioeconomic impact disease. As center P.I. he participated in the group collaborative publications as well as co authoring many individually by-lined papers (Ref. 22, 23, 24, 25, 26, 28, 29, 31, 32, 37, 40, 42). His successful and productive work as a center P.I. on this trial led to the funding for the LIGHT-ROP multi-center trial for which he served as project director and lead P.I. This trial definitively answered a long debated hypothesis in ROP i.e. that ambient light was not a causal factor in ROP (Ref. 38, 41, 45, 47). Dr. Reynolds was again selected as a center P.I. for the next large multi-center ROP trial, ET-ROP, which just reported its primary results demonstrating that earlier laser treatment for this disease was effective. Although all multi-center clinical trials are cooperative agreements at the NIH and thus are funded as UO1s rather than RO1s, Dr. Reynolds was an integral participant in all the ROP trials from the mid-eighties to the present, leading one, and actively co-authoring many of the studies?publications as noted in the bibliography. The future of Dr. Reynolds?ROP research will undoubtedly involve more funded multi-center trials. However, a basic science collaboration into the pathophysiology of ROP in an animal model is planned, investigating the renin-angiotension connection.
Retina; Gene therapy; Neurodegenerative disorders; Pathophysiology; Protein Folding; Gene Expression; Signal Transduction
I am a Clinician Scientist working in the field of hereditary retinal and macular degenerations. I direct a regional referral service for these diseases at the Ross Eye Institute. My NIH- and VA-funded laboratory is focused on the development of gene-based therapeutics for hereditary retinal degenerations and common age-related macular degeneration.
Synopsis Of Research: My research focuses on studying the diabetic related vascular complications, including diabetic retinopathy, diabetic vascular disease, insulin resistance and diabetic nephropathy. In addition to addressing mechanisms, our cellular and biochemical studies are meant to develop cures for diseases that affect the retina, peripheral vessel and kidney. 1.Diabetic retinopathy: Focusing on endoplasmic reticulum (ER) stress activation and interactions among ER stress, oxidative stress and inflammation in retina. 2.Peripheral vascular disease (PVD): Endothelial cells in the vascular system are especially vulnerable to hyperglycemic conditions. Exploring endothelial dysfunction in diabetic setting, would aid in the search for novel approaches in the prevention of diabetes vascular disease. 3.Diabetic nephropathy: Glomerular endothelial cells and podocytes are primary sites of injury resulting in chronic kidney disease in diabetes. We investigate the function of endogenous angiogenic inhibitors in regulation of renal cells in diabetic kidney. 4.Adipocyte and insulin resistance: Studying the function of PEDF in adipogenesis, provide pivotal information for understanding the mechanisms underlying the association of PEDF,obesity and insulin resistance. Selected Publications: 1.Boriushkin E, Wang JJ, Li J, Bhatta M, Zhang SX. p58(IPK) suppresses NLRP3 inflammasome activation and IL-1β production via inhibition of PKR in macrophages. Sci Rep. 2016 Apr 26;6:25013. doi: 10.1038/srep25013. PubMed PMID: 27113095; PubMed Central PMCID: PMC4845006. 2.Bhatta M, Ma JH, Wang JJ, Sakowski J, Zhang SX. Enhanced endoplasmic reticulum stress in bone marrow angiogenic progenitor cells in a mouse model of long-term experimental type 2 diabetes. Diabetologia. 2015 Sep;58(9):2181-90. doi: 10.1007/s00125-015-3643-3. Epub 2015 Jun 11. PubMed PMID: 26063198; PubMed Central PMCID: PMC4529381. 3.Gardner AW, Parker DE, Montgomery PS, Sosnowska D, Casanegra AI, Ungvari Z, Csiszar A, Zhang SX, Wang JJ, Sonntag WE. INFLUENCE OF DIABETES ON AMBULATION AND INFLAMMATION IN MEN AND WOMEN WITH SYMPTOMATIC PERIPHERAL ARTERY DISEASE. J Clin Transl Endocrinol. 2015 Dec 1;2(4):137-143. PubMed PMID: 26835254; PubMed Central PMCID: PMC4730895. 4.Zhang SX, Ma JH, Bhatta M, Fliesler SJ, Wang JJ. The unfolded protein response in retinal vascular diseases: implications and therapeutic potential beyond protein folding. Prog Retin Eye Res. 2015 Mar;45:111-31. doi: 10.1016/j.preteyeres.2014.12.001. Epub 2014 Dec 18. Review. PubMed PMID: 25529848; PubMed Central PMCID: PMC4339403. 5.Chen C, Cano M, Wang JJ, Li J, Huang C, Yu Q, Herbert TP, Handa JT, Zhang SX. Role of unfolded protein response dysregulation in oxidative injury of retinal pigment epithelial cells. Antioxid Redox Signal. 2014 May 10;20(14):2091-106. doi: 10.1089/ars.2013.5240. Epub 2013 Dec 17. PubMed PMID: 24053669; PubMed Central PMCID: PMC3995121 6.Zhang SX, Sanders E, Wang JJ. Endoplasmic reticulum stress and inflammation: mechanisms and implications in diabetic retinopathy. J Ocul Biol Dis Infor. 2011 Jun;4(1-2):51-61. doi: 10.1007/s12177-011-9075-5. Epub 2012 Jan 18. PubMed PMID: 23330021; PubMed Central PMCID: PMC3342410. 7.Wang M, Wang JJ, Li J, Park K, Qian X, Ma JX, Zhang SX. Pigment epithelium-derived factor suppresses adipogenesis via inhibition of the MAPK/ERK pathway in 3T3-L1 preadipocytes. Am J Physiol Endocrinol Metab. 2009 Dec;297(6):E1378-87. doi: 10.1152/ajpendo.00252.2009. Epub 2009 Oct PubMed PMID: 19808909; PubMed Central PMCID: PMC2793046. 8.Wang JJ, Zhang SX, Mott R, Knapp RR, Cao W, Lau K, Ma JX. Salutary effect of pigment epithelium-derived factor in diabetic nephropathy: evidence for antifibrogenic activities. Diabetes. 2006 Jun;55(6):1678-85. PubMed PMID: 16731830. See more publications on http://www.ncbi.nlm.nih.gov/sites/myncbi/1heXcsvGDSdAl/bibliography/41170057/public/?sort=date&direction=ascending.
Clinical Associate Professor, Department of Ophthalmology, University at Buffalo, State University of New York. Dr. Weiner specializes in glaucoma and cataract consultation, laser and surgical therapy. He completed his residency at the Hebrew University and Hadassah University Hospital, Jerusalem, Israel, and in Cleveland OH, and clinical fellowships at the Mass. Eye & Ear Infirmary, Harvard Medical School, Boston, MA, and Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA. Dr. Weiner has published multiple peer-reviewed papers and currently focuses on surgical technique modifications in glaucoma surgery especially in glaucoma tube shunt implantation on which he gave an invited talk at the American Glaucoma Society 2017 Annual Meeting. He has lectured and performed surgeries internationally.
Ophthalmology; Retina; Apoptosis and cell death; Gene Expression; Gene therapy; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Protein Folding; Regulation of metabolism; Signal Transduction; Vision science
The research in my lab has focused on two main areas: 1). molecular mechanisms of inflammation, angiogenesis, vascular and neuronal degeneration in retinal diseases; 2). potential roles of angiogenic inhibitors in obesity, insulin resistance and diabetes. The first line of research centers on gene regulation and signal transduction pathways underlying the neurovascular injury in diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration. In recent years, we are focusing our efforts on the function and mechanism of the UPR signaling in normal and diseased retinal cells. The latter one combines basic and clinical research to study biomarkers and mechanism of type 2 diabetes. 1. ER stress and the UPR signaling in retinal neurovascular injury and diabetic retinopathy. The endoplasmic reticulum (ER) is the primary site for protein synthesis and folding. Failure of this machinery to fold newly synthesized proteins presents unique dangers to the cell and is termed “ER stress.” In response to the stress, cells have evolved an intricate set of signaling pathways named the unfolded protein response (UPR) to restore the ER homeostasis. In addition, the UPR is known to regulates many genes involved in important physiological processes to modulate cell activity and cell fate. The project in my laboratory is aimed to understand the role of ER stress and the UPR in retinal vascular endothelial cell dysfunction and neuronal degeneration in diabetic retinopathy. Our previous work has implicated several key UPR branches such as IRE-XBP1 and ATF4-CHOP in retinal inflammation and vasculopathy in diabetes. Currently, we are employing integrated genetic tools and animal models to study the function of UPR genes in the retina and to dicepher the molecular links between the UPR signaling and inflammatory pathways in retinal cells. Findings from these studies are anticipated to identify novel therapeutic targets and develop new treatments for diabetic retinopathy. 2. Mechanisms and potential therapies for RPE death in age-related macular degeneration. The retinal pigment epithelium (RPE) plays an essential role in maintaining the normal structure and function of photoreceptors. RPE dysfunction and cell death is a hallmark pathological characteristic of age-related macular degeneration (AMD), a disease that accounts for the majority of vision impairment in the elderly. Using transgenic mouse models, we discovered that the transcription factor XBP1 is a critical regulator of oxidative stress and cell survival in RPE cells. Genetic depletion or inhibition of XBP1 sensitizes the RPE to stress resulting in cell death. Our ongoing studies focus on identifying the target genes of XBP1 in RPE cells through which the protein regulates cell survival. We are also investigating if these proteins could offer potential salutary effects to protect RPE cells from oxidative injury and degeneration in disease conditions such as AMD. 3. Roles and mechanisms of angiogenic/anti-angiogenic factors in obesity, insulin resistance and diabetes. Obesity, insulin resistance and Type 2 diabetes are clustered as the most important metabolic disorders, substantially increasing morbidity and impairing quality of life. Excess body fat mass, particularly visceral fat, leads to dysregulation of adipokines (proteins secreted from fat cells), resulting in higher risk of cardiovascular diseases. Our recent findings indicate that angiogenic/anti-angiogenic factors are associated with obesity, diabetes and diabetic complications. For example, pigment epithelium-derived factor (PEDF), a major angiogenic inhibitor, is an active player in adipose tissue formation, insulin resistance and vascular function. In the future, we hope to futher understand the functions and mechanisms of these proteins in lipid metabolism and adiposity. In collaboration with a number of clinical investigators, we are exploring the physiological application of these factors as novel biomarkers and therapeutic targets in the diagnosis and treatment of diabetes, metabolic disorders and peripheral vascular diseases.