Eukaryotic Pathogenesis; Immunology; Infectious Disease; Microbial Pathogenesis; Microbiology; Molecular Basis of Disease; Signal Transduction; Vision science
Toxoplasma gondii is an obligate intracellular parasite that has the unique ability of infecting most nucleated cells in almost all warm-blooded animals. It is one of the most widespread infections in the world: approximately 50 percent of the world‘s population is infected. Luckily, most infected people are asymptomatic; however, in AIDS patients and other immune-compromised individuals, Toxoplasma causes serious and life-threatening disease. Besides its own medical importance, we study Toxoplasma because it represents an ideal model system to study how other related pathogens cause disease. These include Plasmodium, which is the causative agent of malaria that is responsible for millions of deaths worldwide, and Cryptosporidium, which causes another important secondary infection in AIDS patients. Toxoplasma is a great model system because it can easily be grown in vitro, its genome has been sequenced and it can be genetically manipulated. My research team and I are focused on two different but related questions. First, we want to know how the parasite grows inside of its host cell. One of the important things Toxoplasma must do to grow is hijack host cell pathway and factors. We are using functional genomic assays such as microarrays and genome-wide RNA interference (RNAi) screens to identify these host factors. Identifying them is important because if the parasite cannot use these pathways, the parasite will not grow or cause disease. Thus, these pathways represent novel drug targets. As an example, we discovered that oxygen-regulated transcription factors in the host cell are necessary to support parasite growth. We are currently identifying how these transcription factors function and how the parasite adapts to the various oxygen environments it encounters during its lifecycle. Second, we want to know how Toxoplasma affects the central nervous system and how anti-Toxoplasma immune responses function in the central nervous system. These questions are important because Toxoplasma primarily causes disease in the brain and retina. Our work has revealed that when Toxoplasma actively grows in the brain (a condition known as toxoplasmic encephalitis), it causes a massive reorganization of inhibitory synapses. These changes inhibit GABAergic synaptic transmission and this inhibition is a major factor in the onset of seizures in infected individuals. A second line of research using an ocular infection model has focused on defining how immune responses in the central nervous system are generated by Toxoplasma and then resolved once the infection is under control.
I am interested in bringing people together who have an interest in anatomy but are trained as educators, artists, computer scientists programmers or graphical designers. For example, a graphical artist by training completed a master’s degree in our department by designing a computer-based tutorial on the anatomy of the renal corpuscle. Other projects I have worked on include a computer-guided program of instruction for the histology laboratory (see http://www.buffalo.edu/news/3016), a highly interactive computer-based examination that has a broad range of applicability, and a computer-based video examination. In the future I expect to introduce virtual microscopy to our course in histology. I am also interested in the evaluation of computer assisted instruction and the way CAI contributes to learning.
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.
Cardiovascular Disease; Diagnostic Radiology; Neuroradiology - Radiology; Radiological Physics; Vascular and Interventional Radiology; Vision science
My research career focuses on improvement of endovascular image guided interventions and encompasses three major components: vascular disease research, endovascular device development and medical imaging. Since the beginning of my research I tried to develop and test endovascular device in patient relevant physiology in a lab setting. I developed the first balloon deployable asymmetric flow diverters nearly eight years ago and test them in idealized aneurysms phantoms. Over the years with my collaborators at Toshiba Stroke and Vascular Research Center (TSVRC), I developed an entire chain of manufacturing and testing of such devices. Concerning imaging, my research is focused on physiological conditions determination based on imaging such as angiography and CT and micro-CT.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular genetics; Stem Cells; Transcription and Translation; Transgenic organisms; Vision science
My lab is interested in how global gene expression advances from one state to the next in time and space during development to promote the specification and differentiation of individual retinal cell types from multi-potent neural progenitor cells. We focus on the gene regulatory network (GRN) involved in the formation of one retinal cell type, retinal ganglion cells (RGCs). RGCs are the only projection neurons in the retina and connect the retina to the brain through the optic nerve. Death of RGCs is cause of vision loss in glaucoma and other retinal diseases. Several key transcription factors (TFs) functioning at different stages of RGC development have been identified; Math5 is essential for RGC fate specification, whereas Pou4f2 and Isl1 are required for their differentiation. Our previous study has established a tentative model for the RGC GRN, in which these TFs occupy key node positions. Current projects in the lab are aimed at further understanding how these transcription factors specifically regulate their target genes and how they interact with each other. Considerable efforts are also placed on identifying novel key regulators in the GRN. Our studies employ a combined approach of genetics, genomics and bioinformatics. Our eventual goal is to use the knowledge learned from our studies to develop new therapies for various retinal diseases.
Inherited Metabolic Disorders; Membrane Transport (Ion Transport); Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Transgenic organisms; Vision science
Most physiological processes and numerous disease states influence or are influenced by pH. Even relatively small deviations in whole body pH can have devastating consequences for our health. Our bodies are subject to a constant challenge from dietary and metabolic acids, thus it is critical for the body to have mechanisms that tightly regulate pH. Blood plasma pH is maintained at a value close to 7.4, predominantly thanks to the buffering action of 24 mM bicarbonate (HCO3-). HCO3- neutralizes acid, generating carbon dioxide and water (HCO3- + H+ to CO2 + H2O), preventing lethal acidosis. I study the SLC4 family of membrane proteins that move HCO3- across cell membranes. Notable members include  the Na/2HCO3 cotransporter NBCe1-A that reclaims HCO3- from filtered blood plasma in kidney tubules (preventing loss of vital plasma HCO3- to the urine),  NBCe1-B that promotes fluid removal from the corneal stroma (preventing corneal edema and vision loss),  the Cl-HCO3 exchanger AE1 that promotes O2-CO2 exchange in red blood cells, and  SLC4A11 that conducts H+ and promotes corneal clarity. Dysfunction of SLC4 family members is associated with renal tubular acidosis, blindness, cancer, deafness, epilepsy, and hypertension.
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.
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.