The long term goal of the research in my lab is to elucidate the mechanisms of retinal development and disease at transcriptional and posttranscriptional levels, focusing on noncoding RNAs, singaling moleculres, transcription factors and small molecules. Our research mainly focuses on a disease called age-related macular degeneration (AMD). AMD is the leading cause of blindness in the elderly, affecting ~8.7% percent of the worldwide population. AMD has two forms: neovascular (wet) AMD and dry AMD. Wet AMD, which accounts for the majority of acute vision loss in AMD, is characterized by choroidal neovascularization (CNV), a process involving abnormal growth of blood vessels from the choroid into the retina. Current drugs anti-VEGF agents can improve the clinical outcome of wet AMD, but unable to induce complete disease regression. The late stage of dry AMD, known as geographic atrophy (GA), is characterized by extensive loss of retinal pigment epithelium (RPE) cells. There is currently no cure available for dry AMD. In the past years, our research has shed light on the mechanism of microRNAs and long noncoding RNAs (lncRNA) in retinal vascular development and disease, as well as the mechanism of RPE cell death and senescence in response to AMD-related oxidative stress.
Role of noncoding RNAs in ocular angiogenesis
Ocular angiogenesis plays a central role in eye development and in many major retinal vascular diseases, such as retinopathy of prematurity, diabetic retinopathy (DR) and age-related macular degeneration (AMD).
In the last several years, the research in our lab has found that:
- An EC-enriched miRNA miR-126 is crucial to govern vascular integrity and ocular angiogenesis (Wang et al, 2008; Developmental Cell; Zhou et al, 2016, Molecular Therapy). Particularly, we found a strand- and cell type-specific function of miR-126 in ocular angiogenesis.
- There are critical but distinct roles of miR-23~27~24 cluster members in ocular angiogenesis and in wet AMD mouse models. Specifically, miR-23 and miR-27 in the cluster are required for proper ocular angiogenesis (Zhou et al., 2011, Proceedings of the National Academy of Sciences), while miR-24 represses ocular neovascularization through actin cytoskeleton pathways (Zhou et al., 2013, Molecular Therapy).
- A collaborative effort has found that miR-146a is upregulated during retinal pigment epithelium (RPE)/choroid aging in mice and represses IL-6 and VEGF-A expression in RPE cells (Hao et al., 2016, Journal of Clinical and Experimental Ophthalmology).
- Recently we discovered that a long noncoding RNA (lncRNA) lncEGFL7OS is required for angiogenesis by regulating the expression of microRNA in humans (Zhou and Yu et al, 2019, Elife).
Ongoing studies are focused on studying the role of miRNAs and other noncoding RNAs in ocular development and disease models.
Cell death and Senescence mechanism of RPE cells and their implications in AMD
Geographic atrophy (GA) is a late stage dry AMD characterized by scattered or confluent areas of retinal pigment epithelial (RPE) cell degeneration. GA accounts for 35% of all cases of late-stage AMD and 20% of legal blindness attributable to AMD and without cure available. RPE cell death and senescence induced by oxidative stress has been hypothesized to drive AMD pathogenesis. The underlying mechanisms are currently unclear.
- To clarify the controversy, we have recently demonstrated that, necroptosis, but not apoptosis, is a major type of cell death in RPE cells in response to oxidative stress in vitro and in vivo (Hanus et al., 2013, Cell Death & Disease; Hanus et al., 2016, Cell Death Discovery).
- To identify novel small molecules that prevent oxidative stress-induced RPE cell death, we conducted a chemical screening of a library with 1840 FDA-approved drugs and natural products. We have identified several compounds that can prevent oxidative stress-induced RPE cell death, including a known antioxidant ebselen, an unknown 4-acetoxyphenol (4-AC), and a male contraceptive, Gossypol-Acetic Acid complex (GAA) (Hanus et al, 2015. Molecular and Cellular Biology; Hanus et al., 2015, Investigative Ophthalmology & Visual Science). We hope to repurpose these existing FDA-approved drugs and test them as novel anti-AMD drugs using preclinical AMD animal models.
- To study the genetic mechanisms of senescence, we found that a mitochondrial phosphatase PGAM5 is required to prevent RPE senescence by regulating mitochondrial dynamics (Yu et al, 2020, Nature Communications).