1) Role of microRNA-183/96/182 cluster in Pseudomonas aeruginosa (PA)-induced keratitis

1A) Role of miR-183C modulating PA-induced keratitis and regulation of innate immunity

2A) Regulation of sensory innervation

3A) Neuroimmune interactions

2) Influence of miR-183C on Corneal Biology

There are multiple types of corneal resident immune cells (CRICs) reported in the cornea, and they play important roles in normal development and homeostasis. We utilized single-cell RNA sequencing to study the transcriptomes of individual cells and dissect the molecular complexity of CRICs, as well as the role of miR-183C in shaping the corneal cellular landscape. First, we discovered that the diversity of CRICs is enhanced with age. Additionally, we found that naïve mouse cornea contains previously unrecognized resident fibrocytes and neutrophils under homeostatic conditions. Resident macrophages (ResMφ) were reprogrammed to support the structure and functions of the cornea by expressing genes important for extracellular matrix organization. We also found that miR-183C limited the diversity and polarity of ResMφ; however, inactivation of miR-183C disrupts the stability of the major cell-type composition and age-related transcriptomic shifts of subtypes of corneal cells. For instance, there are enhanced numbers of monocytes, dendritic cells, and neutrophils among corneal resident myeloid cells as well as all subtypes of corneal resident lymphocytes in the miR-183C KO mice compared to wildtype littermates (Ocular Surface 2023).

3) Role of microRNA in Dry Eye Disease (DED)

It has been shown that inactivation of miR-183C in a conventional KO mouse model results in decreased nerve density and reduced pro-inflammatory expression in the cornea (IOVS 2016). Most recently, we demonstrated that the inactivation of miR-183C in a sensory neuron-specific conditional knockout (SNS-CKO) has similarly resulted in decreased sensory nerve density and decreased corneal sensitivity to mechanical stimuli (Scientific Reports 2024; paper pending). Additionally, our recent data suggest that miR-183C modulates basal tear production through its regulation of corneal sensory innervation. Tear volume was significantly decreased in both the miR-183C KO and SNS-CKO mice compared to their WT littermates. Interestingly, we found that the male mice exhibited greater decreases in tear volume compared to the female mice (Scientific Reports 2024; paper pending). This observed sex-related difference in tear production aligns with the finding that female gender has been considered a risk factor for the development of DED.

4) Role of microRNA in Inherited Retinal Degeneration

Identification of disease-causing mutations in the miR-183/96/182 cluster in human. Previously, we have shown that inactivation of miR-183/96/182 cluster in mice results in multi-sensory defects, including retinal degeneration and blindness, deafness and balancing deficit, as well as changes in both the innate and adaptive immunity. We hypothesize that mutations in human cause syndromic retinal degeneration with involvement of multisensory domains and immune and autoimmune complications. We have established a collaboration with EyeGene – a NEI, NIH-operated tissue depository for patients with inherited retinal dystrophies. We are currently performing mutation screening in these patients. We are seeking to expand the collaborations of physician scientists in different fields, e.g., ophthalmology and immune/autoimmune diseases, to identify human disease(s) caused by mutations in the miR-183/96/182 cluster. If successful, we will identify the molecular basis for these diseases and develop new gene diagnosis and therapy.

5) Role of microRNA in Diabetic Retinopathy

In other research, we reported the first systemic studies on miRNAs in diabetic retinopathy (DR) and identified a series of miRNAs involved in early DR (IOVS 2011). This report is recognized to “provide the first insight into the roles of miRNAs in the pathogenesis of DR” by peers in the field. We further showed that miR-146 has a negative feedback regulation on the interleukin 1 receptor (IL-1R)/Toll-like receptor (TLR)-mediated as well as G-protein-coupled receptor (GPCR)-mediated NF-kB activation pathways in RECs through targeting key adaptor molecules of these pathways (IOVS 2014). Recently our in vivo study in a diabetic rat model showed that intraocular delivery of miR-146 suppressed NF-kB activation pathways, and inhibited diabetes-induced upregulation of pro-inflammatory factor and retinal microvascular and neuronal functional defects (IOVS 2017), providing proof-of-principle evidence that miR-146 is a potential therapeutic target for treatment of DR.

6) Role of microRNA in Age-related Ocular Disease

Research Support

Current: National Eye Institute (NEI), National Institutes of Health (NIH): R01 EY02605902 (PI), R01EY016058 and P30EY004068 (Co-I. PI: Linda D. Hazlett).

Unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology, Visual and Anatomical Science, Wayne State University School of Medicine (PI: Mark Juzych)

Bridge fund from the Office of Vice President for Research (OVPR) of the Wayne State University

Past support: American diabetes association (ADA), Eversight, Brightfocus Foundation (Former American Health Assistance Foundation), Juvenile Diabetes Research Foundation (JDRF), Glaucoma Research Foundation, American Cancer Society, St. Baldrick Foundation, Michael J. Fox foundation. Alliance for Vision Research, Lincy Foundation.