Position Title

Associate professor

Biography

The research interest of my lab is to study the roles of microRNAs (miRNAs) in the eye and ocular diseases. miRNAs are small, non-coding, regulatory RNAs and constitute a newly recognized level of gene expression regulation. Our long-term goal is to uncover the roles miRNAs in normal development and function of the eye, as well as in ocular diseases so as to identify novel miRNA-based therapeutic targets for the treatment of various ocular diseases.

We reported one of the first miRNA transcriptomes in mouse retina, and identified a conserved paralogous miRNA cluster, the miR-183/96/182 cluster, in the retina and other sensory organs (JBC, 2007). We solved the genomic structure of the miR-183/96/182 cluster gene and demonstrated that inactivation of the miR-183/96/182 cluster gene results in syndromic retinal degeneration with multiple sensory defects (PNAS, 2013; Sci Rep, 2018).

In addition, we discovered that the miR-183/96/182 cluster is also expressed in the cornea, and in the innate immune cells, including neutrophils and macrophages; inactivation of the cluster in mice results in a decreased inflammatory response and reduced severity of Pseudomonas aeruginosa-induced keratitis, providing the first evidence that the miR-183/96/182 cluster plays an important role in innate immune functions and the corneal response to P. aeruginosa infection (IOVS, 2016). Furthermore, with our collaborators, we discovered that that miR-183/96/182 cluster is expressed in Th17 and iNKT cells and promotes Th17 pathogenicity (Immunity, 2016) and plays important roles in iNKT cell development, maturation and effector functions (J Immunol, 2019).

Recently, our new discoveries demonstrated that the corneal resident macrophages are innate IL-17- and IL-10-producing cells; miR-183/96/182 cluster regulates the production of both, as well as the number of steady-state corneal resident macrophages and retinal microglia and the dynamics of innate immune cell infiltration during P. aeruginosa keratitis (ImmunoHorizon. 2020). This is the first example that a miRNA cluster regulates tissue resident macrophage population and their functions in any tissue. This discovery has a profound implication to the roles of miRNAs in innate immunity, since tissue resident macrophages play critical roles in the homeostasis, tissue repair and remodeling and oncogenesis.

On another line of 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, inhibited diabetes-induced upregulation of pro-inflammatory factor and retinal microvascular and neuronal functional defects (IOVS 2017), providing a proof-of-principle evidence that miR-146 is a potential therapeutic target for treatment of DR.

 

• 1992. The Young Investigator Award, first prize, Chinese Association of Genetics, Beijing for the excellent research work on “a new procedure for DMD/BMD diagnosis-Amp-FLP linkage analysis”.
• 1994. The Outstanding Achievement Award in The Development Of Advanced Sciences And Technology by the Department of Health, People’s Republic of China, for the outstanding study on “Gene Diagnosis of Duchenne / Becker Muscular Dystrophy”.
• 1995. The Outstanding Achievement Award in Advanced Sciences And Technology by the State Science And Technology Commission, People’s Republic of China, for the pioneer work on Prenatal Diagnosis and Genetic Analysis of Duchenne / Becker Muscular Dystrophy.
• 2007. Faculty of 1000 Biology. Our paper entitled “The proliferation and expansion of retinal stem cells require functional Pax6” (Xu S, et al. Dev Biol. 2007 304(2):713-21), was selected because of its high scientific merit and impact. June 2007.
• 2011. Young Investigator award. 7th Congress of the Federations of Asian and Oceanian Physiological Societies (FAOPS). microRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats.
• 2018-present Research Grant Review Committee, Eversight Foundation
• 2016-present Research Grant Review Committee (RGRC), American Diabetes Association (ADA).
• 2020 – present Frontiers in Aging Neuroscience
• 2020 – present Pathogens

 

Education

• 2002 – 2004. Postdoctoral fellow, Laboratory of Dr. Derek van der Kooy. Dept of Medical Genetics & Microbiology. University of Toronto
• 2000 – 2002 Postdoctoral fellow, Laboratory of Dr. David Valle. Howard Hughes Med Inst/Johns Hopkins U. School of Medicine.
• 1995-2000. Ph.D. Predoctoral Training Program in Human Genetics, the Johns Hopkins University School of Medicine
• 1993 – 1995 Postdoctoral fellow, Laboratory of Richard A. Gatti, Dept of Pathology and Laboratory Medicine. University of California, Los Angeles School of Medicine
• 1991 - 1993 Research associate, Section of Molecular Genetics, Dept of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Med Sci/Peking Union Medical College
• 1986-1991. M.D. Peking Union Medical College (PUMC)
• Aug-Oct, 1989 Internship (as an exchange student from PUMC), University of California, San Francisco, School of Medicine
• 1983-1986 pre-med. Beijing University

 

Faculty Appointments

• 7/2013-present Associate Professor, Department of Ophthalmology/Kresge Eye Institute, and Department of Anatomy & Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan (tenured from 8/2019)
• 2004 – 6/2013 Assistant Professor. Depts of Pharmacology, Ophthalmology, Neurological Sciences, Rush University Medical Center, Chicago

   

Research

 Current research projects

1) The potential and mechanisms of the miR-183/96/182 cluster as a therapeutic target for treatment of P. aeruginosa-induced keratitis: P. aeruginosa-induced keratitis is one of the most rapidly developing and destructive diseases of the cornea and a global cause of visual impairment and blindness. P. aeruginosa is one of the most common causative organisms of contact lens-related disease in developed countries. Although antibiotic treatment reduces the bacterial burden, tissue damage often occurs as a result of a poorly controlled host immune response. Previously we showed that inactivation of the cluster results in a decreased inflammatory response and reduced severity of P. aeruginosa-induced keratitis. We hypothesize that downregulation of the miR-183/96/182 cluster in the cornea by anti-miR-183/96/182 has a therapeutic effect on P. aeruginosa keratitis. We are currently testing this hypothesis and study the mechanism underlying the therapeutic effect. Possible mechanisms include enhancement of innate immunity and neuroimmune interactions.

2) The roles of miR-183/96/182 cluster in corneal resident macrophages and retinal microglial cells and in chronic inflammation of ocular tissues. Tissue resident macrophages play an important role in the homeostasis of the cornea and the retina. Activation of the tissue resident macrophages induces chronic inflammation, a process common to a multitude of eye diseases, including dry eye disease, corneal wound healing, diabetic retinopathy, age-related macular degeneration and glaucoma. We have shown that miR-183/96/182 cluster has a regulatory role in the numbers of steady-state corneal resident macrophages and retinal microglia – resident macrophages in the retina and the cytokine-production function of corneal resident macrophages. We hypothesize that miR-183/96/182 cluster may have a significant modulatory role in a multitude of eye diseases through its regulation on corneal resident macrophages and retinal microglia. Currently, we are testing this hypothesis and the molecular mechanisms underlying its regulation on tissue resident macrophages with cutting edge technologies, e.g. single cell RNA sequencing and Ago-HITS-CLIP.

3) The roles of miR-183/96/182 cluster in neuro-immune interaction and related diseases. The miR-183/96/182 cluster plays important roles in both the sensory and immune systems, providing a link between these two defensive systems. The miR-183/96/182 cluster may have a pivotal role in the neuroimmune interactions in different tissue/organs. Its regulation on the neuroimmune interaction may have significant impact on the homeostasis of the cornea and the retina and their immune/inflammatory response to microbial infection and other insults and contribute to a multitude of corneal and retinal degenerative diseases. We are currently dissecting the roles of miR-183/96/182 cluster in neuroimmune interaction using various cell-type-specific conditional knockout mice in the P. aeruginosa keratitis model.

4) 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) Genomic structure of the miR-183/96/182 cluster gene in human genome and characterization of the functions of the transcripts of this gene. Previously, we solved the genomic structure of the miR-183/96/182 cluster gene in mouse. In mouse genome, the miR-183/96/182 cluster gene produced two alternatively spliced isoforms. The miR-183/96/182 cluster itself resides in the intron. Whether the two transcripts are long non-coding RNAs or encode small peptides is still an unanswered question and could be fundamental to the understanding of its functions. The human genomic structure of the miR-183/96/182 cluster gene has been solved yet. Characterization of the genomic structure of miR-183/96/182 cluster gene will shed new light into the conservation of the gene and significance and functions of the transcripts.

Research support

Current: National Eye Institute (NEI), National Institutes of Health (NIH): R01EY026059 (PI), R01EY016058 (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)

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.

 

Links of Interest

Kresge Eye Institute

Selected publications

1. Xu S, Coku A, Muraleedharan CK, Harajli A, Mishulin E, Dahabra C, Choi J, Garcia WJ, Webb K, Birch D, Goetz K, Li W. Mutation screening in the miR-183/96/182 cluster in patients with inherited retinal dystrophy. Frontiers Cell and Developmental Biology, 2020 Dec 23; 8:619641. Doi:10.3389/fcell.2020.619641. PMID: 33425925; PMCID: PMC7785829.

2. Coku A, McClellan SA, VanBuren E, Back JB, Hazlett LD, Xu S. The miR-183/96/182 cluster regulates the functions of corneal resident macrophages. ImmunoHorizons 2020 Nov 18;4(11):729-744. doi: 10.4049/immunohorizons.2000091. PMID: 33208381.

3. Zhuang P, Zhang H, Welchko RM, Thompson RC, Xu S, and Turner DL. Combined microRNA and mRNA detection in mammalian retinas by in situ hybridization chain reaction. Sci Rep. 2020 Jan 15;10(1):351. doi: 10.1038/s41598-019-57194-0. PMID: 31942002. DOI:10.1038/s41598-019-57194-0.

4. Wang J, Li G, Wu X, Liu Q, Yin C, Brown S, Xu S, Mi Q, and Zhou L. MiR183-96-182 cluster is involved in invariant NKT cells development, maturation and effector function. J Immunol 2019 Dec 15;203(12):3256-3267. doi: 10.4049/jimmunol.1900695. Epub 2019 Nov 20. PMID: 31748350. DOI:10.4049/jimmunol.1900695.

5. Xu S, Hazlett LD. microRNAs in Ocular Infection. Microorganisms. 2019 Sep 17;7(9). pii: E359. doi: 10.3390/microorganisms7090359. Review. PMID: 31533211. Impact factor: 4.167.

6. Pucella JN, Cols M, Yen W, Xu S, and Chaudhuri J. The B Cell Activation-Induced miR-183 Cluster Plays a Minimal Role in Canonical Primary Humoral Responses. J of Immunology. 2019 Jan 25. pii: ji1800071. doi: 10.4049/jimmunol.1800071. PMID:30683701.

7. Geng R, Furness DN, Muraleedharan CK, Zhang J, Dabdoub A, Lin V, Xu S. The microRNA-183/96/182 Cluster is Essential for Stereociliary Bundle Formation and Function of Cochlear Sensory Hair Cells. Scientific report. 2018 Dec 21;8(1):18022. doi: 10.1038/s41598-018-36894-z. PMID: 30575790. PMCID: PMC6303392.

8. Muraleedharan CK, McClellan, Ekanayaka SA, Francis R, Zmejkoski A, Hazlett LD, and Xu S. The miR-183/96/182 Cluster Regulates Macrophage Functions In Response to Pseudomonas aeruginosa. Journal of Innate Immunity. 2019 Jan 9:1-12. doi: 10.1159/000495472. PMID: 30625496. DOI: 10.1159/000495472.

9. Zhuang P, Muraleedharan CK, Xu S. Intraocular delivery of miR-146 inhibits diabetes-induced retinal functional defects in diabetic rat model. IOVS. 2017; 58:1646-1655. PMID: 28297724.

10. Liu WH, Kang SG, Huang Z, Wu CJ, Jin HY, Maine CJ, Liu Y, Shepherd J, Sabouri-Ghomi M, Gonzalez-Martin A, Xu S, Hoffmann A, Zheng Y, Lu LF, Xiao N, Fu G, Xiao C. A miR-155-Peli1-c-Rel pathway controls the generation and function of T follicular helper cells. J Exp Med. 2016 Aug 1; 213(9): 1901–1919. PMID: 27481129. PMCID: PMC4995083 11. Ichiyama K, Gonzalez-Martin A, Kim BS, Jin HY, Jin W, Xu W, Sabouri-Ghomi M, Xu S, Zheng P, Xiao C, Dong C. The MicroRNA-183-96-182 Cluster Promotes T Helper 17 Cell Pathogenicity by Negatively Regulating Transcription Factor Foxo1 Expression. Immunity 2016;44:1284-98. PMID: 27332731. PMCID: PMC4918454

12. Muraleedharan CK, McClellan SA, Barrett RP, Li C, Montenegro D, Carion T, Berger E, Hazlett LD, and Xu S. Inactivation of the miR-183/96/182 cluster decreases the severity of Pseudomonas aeruginosa-induced keratitis. Invest Ophthalmol Vis Sci. 2016 Apr 1;57(4):1506-17. doi: 10.1167/iovs.16-19134. PMID: 27035623 13. Xu S. microRNAs and inherited retinal dystrophies. Proc Natl Acad Sci U S A. 2015 Jul 9. pii: 201511019. [Epub ahead of print]. PMID:26159420. (Invited commentary) 14. Albers MW, Gilmore GC, Kaye J, Murphy C, Wingfield A, Bennett DA, Boxer AL, Buchman AS, Cruickshanks KJ, Devanand DP, Duffy CJ, Gall CM, Gates GA, Granholm AC, Hensch T, Holtzer R, Hyman BT, Lin FR, McKee AC, Morris JC, Petersen RC, Silbert LC, Struble RG, Trojanowski JQ22, Verghese J, Wilson DA, Xu S, Zhang LI. At the interface of sensory and motor dysfunctions and Alzheimer's disease. Alzheimers Dement. 2015 Jan;11(1):70-98. doi: 10.1016/j.jalz.2014.04.514. Epub 2014 Jul 9. PMID: 25022540

15. Cowan C, Muraleedharan CK, O’Donnell JJ, III, Singh PK, Lum H, Kumar A, and Xu S. microRNA-146 Inhibits Thrombin-induced NF-kB Activation and Subsequent Inflammatory Responses in Human Retinal Endothelial Cells. Invest Ophthalmol Vis Sci. 2014 Jul 1;55(8):4944-51. PMID: 24985472.

16. Lumayag S, Haldin CE, Corbett NJ, Wahlin KJ, Cowan C, Turturro S, Larsen P, Kovacs B, Witmer PD, Valle D, Zack DJ, Nicholson DA, and Xu S. Inactivation of the microRNA-

183/96/182 cluster results in syndromic retinal degeneration. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):E507-16. doi: 10.1073/pnas.1212655110. Epub 2013 Jan 22.. PMID: 23341629.

17. Kovacs B, Lumayag S, Cowan C, Xu S. microRNAs in early diabetic retinopathy. Invest Ophthalmol Vis Sci. 2011 Jun 21;52(7):4402-9. PMID: 21498619. 18. Li X, Gibson G, Kim JS, Kroin J, Xu S, van Wijnen AJ, Im HJ. MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis. Gene. 2011 Jul 1;480(1-2):34-41. Epub 2011 Mar 21. PMID:21397669. 19. Xu S. microRNA expression in the eyes and their significance in relation to functions. Prog Retin Eye Res. 2009 Feb;50(2):793-800. Epub 2008 Sep 12. (invited review)

20. Perez SE, Lumayag S, Kovacs B, Mufson EJ and Xu S. (2008) b-Amyloid Deposition and Functional Impairment in the Retina of the APPswe/PS1∆E9 Transgenic Mouse Model of Alzheimer’s Disease. Invest Ophthalmol Vis Sci. 2009 Feb;50(2):793-800.

21. Xu S*, Witmer D, Kovacs B, Lumayag S and Valle D*. (2007). MicroRNA Transcriptome Of Mouse Retina And Functional Study of a Sensory Organ Specific miRNA cluster. J Biol Chem. 282(34):25053-25066. (*: corresponding authors)

22. Liu H, Xu S, Wang Y, Mazerolle C, Thurig S, Coles BLK, Ren J, Taketo MM, van der Kooy D, Wallace VA. (2007). Ciliary margin transdifferentiation from neural retina is controlled by canonical Wnt signaling, Developmental Biology 308(1):54-67.

23. Xu S*, Sunderland ME, Coles BL, Kam A, Holowacz T, Ashery-Padan R, Marquardt T, McInnes RR, van der Kooy D*. (2007). The proliferation and expansion of retinal stem cells require functional Pax6. Dev Biol. 304(2):713-21. (*: corresponding authors) 24. Smukler SR, Runciman SB, Xu S, van der Kooy D. (2006). Embryonic stem cells assume a primitive neural stem cell fate in the absence of extrinsic influences. J Cell Biol. 172(1):79-90.

25. Xu S, Wang Y, Zhao H, Zhang L, Xiong W, Yau KW, Hiel H, Glowatzki E, Ryugo DK, Valle D. (2004). PHR1, a PH Domain-Containing Protein Expressed in Primary Sensory Neurons. Mol Cell Biol. 24:9137-51.

26. Xu S, Ladak R, Swanson DA, Soltyk A, Sun H, Ploder L, Vidgen D, Duncan AM, Garami E, Valle D, McInnes RR. (1999). PHR1 encodes an abundant, pleckstrin homology domain-containing integral membrane protein in the photoreceptor outer segments. J Biol Chem 10;274(50):35676-85.

27. Udar NS*, Xu S*, Bay JO, Dandekar SS, Patel N, Chen X, Liang TY, Uhrhammer N, Klisak I, Shizuya H, Yang H, Samara G, Nelissen J, Sawicki M, Concannon P, Gatti RA. (1999) Physical map of the region surrounding the ataxia-telangiectasia gene on human chromosome 11q22-23. Neuropediatrics 30(4):176-80. (*equal contributions)

 

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