Jacobs School of Medicine & Biomedical Sciences
Apoptosis and cell death; Gene Expression; Gene Therapy; Metabolism; Molecular and Cellular Biology; Molecular Basis of Disease; Neurobiology; Ophthalmology; Protein Folding; Retina; 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.