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Inhibition of RhoA/Rho-kinase pathway suppresses the expression of extracellular matrix induced by CTGF or TGF-β in ARPE-19

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International Journal of Ophthalmology(English edition) 2013年第1期6卷 8-14页

作者： Jing Zhu Duy Nguyen Hong Ouyang Xiao-Hui Zhang Xiao-Ming Chen Kang Zhang Department of Ophthalmology West China Hospital Sichuan University Department of Ophthalmology and shiley eye Center and Institute for Genomic MedicineUniversity of California San Diego Beijing institute of Ophthalmology Beijing Tongren Eye CenterCapital Medical University

AIM:To investigate the role of Rho-associated protein kinase (ROCK) inhibitor, Y27632, in mediating the production of extracellular matrix (ECM) components including fibronectin, matrix metallo-proteinase-2 (MMP-2) and type I collagen as induced by connective tissue growth factor(CTGF) or transforming growth factor-β (TGF-β) in a human retinal pigment epithelial cell line, ARPE-19. METHODS:The effect of Y27632 on the CTGF or TGF-β induced phenotype in ARPE-19 cells was measured with immunocytochemistry as the change in F-actin. ARPE-19 cells were treated with CTGF (1, 10, 100ng/mL)and TGF-β (10ng/mL) in serum free media, and analyzed for fibronectin, laminin, and MMP-2 and type I collagen by RT-qPCR and immunocytochemistry. Cells were also pretreated with an ROCK inhibitor, Y27632, to analyze the signaling contributing to ECM production. ·RESULTS:Treatment of ARPE-19 cells in culture with TGF-β or CTGF induced an ECM change from a cobblestone morphology to a more elongated swirl pattern indicating a mesenchymal phenotype. RT-qPCR analysis and different gene expression analysis demonstrated an upregulation in expression of genes associated with cytoskeletal structure and motility. CTGFor TGF-β significantly increased expression of fibronectin mRNA (P =0.006, P =0.003 respectively), laminin mRNA (P =0.006, P =0.005), MMP-2 mRNA (P =0.006, P =0.001), COL1A1 mRNA (P =0.001, P =0.001), COL1A2 mRNA (P = 0.001, P =0.001). Preincubation of ARPE-19 with Y27632 (10mmol/L) significantly prevented CTGF or TGF-β induced fibronectin (P=0.005, P=0.003 respectively), MMP-2 (P = 0.003, P =0.002), COL1A1 (P =0.006, P =0.003), and COL1A2 (P =0.006, P =0.004) gene expression, but not laminin (P =0.375, P =0.516). CONCLUSION:Our study demonstrated that both TGF-β and CTGF upregulate the expression of ECM components including fibronectin, laminin, MMP-2 and type I collagen by activating the RhoA/ROCK signaling pathway. During this process, ARPE-19 cells were shown to change from an epith

关键词： Rho-associated protein kinase inhibitor Connective tissue growth factor transforming growth factor-β proliferative vitreoretinopathy

Public impact, prevention, and treatment of cataracts

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Science China(Life Sciences) 2015年第11期58卷 1157-1159页

作者： WU Frances WANG Sha ZHU Jie RUTGARD Jeff YAN Yong-Bin ZHANG Kang ZHAO Ling shiley eye institute Department of Ophthalmology and Institute for Genomic Medicine University of California San Diego State Key Laboratory of Membrane Biology School of Life Sciences Tsinghua University State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat-sen University institute of Molecular medicine Peking University

The human lens is composed anteriorly of a single layer of epithelial cells,which undergo mitosis and migrate to the lens equator where they differentiate into lens fiber cells[1].The elongated lens fiber cells expres... 详细信息

关键词：白内障治疗预防纤维细胞晶体蛋白晶状体上皮细胞有丝分裂

Big DNA as a tool to dissect an age-related macular degeneration-associated haplotype

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Precision Clinical medicine 2019年第1期2卷 1-7页

作者： Jon M.Laurent Xin Fu Sergei German Matthew T.Maurano Kang Zhang Jef D.Boeke institute for Systems Genetics Department of Biochemistry and Molecular Pathology Department of Pathology NYU Langone Health shiley eye institute UCSD School of Medicine

Age-related Macular Degeneration(AMD)is a leading cause of blindness in the developed world,especially in aging populations,and is therefore an important target for new therapeutic ***,there have been several studies demonstrating strong associations between AMD and sites of heritable genetic variation at multiple loci,including a highly significant association at *** 10q26 risk region contains two genes,HTRA1 and ARMS2,both of which have been separately implicated as causative for the disease,as well as dozens of sites of non-coding *** date,no studies have successfully pinpointed which of these variant sites are functional in AMD,nor definitively identified which genes in the region are targets of such regulatory *** order to efficiently decipher which sites are functional in AMD phenotypes,we describe a general framework for combinatorial assembly of large‘synthetic haplotypes’along with delivery to relevant disease cell types for downstream functional *** demonstrate the successful and highly efficient assembly of a first-draft 119kb wild-type‘assemblon’covering the HTRA1/ARMS2 risk *** further propose the parallelized assembly of a library of combinatorial variant synthetic haplotypes covering the region,delivery and analysis of which will identify functional sites and their effects,leading to an improved understanding of AMD *** anticipate that the methodology proposed here is highly generalizable towards the difficult problem of identifying truly functional variants from those discovered via GWAS or other genetic association studies.

关键词： CRISPR gene editing synthetic biology age related macular degeneration HTRA1

Retinal microvasculature is a potential biomarker for acute mountain sickness

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Science China(Life Sciences) 2023年第6期66卷 1290-1302页

作者： Yuan Xie Diya Yang Alex S.Huang Yiquan Yang Ying Han Yunxiao Sun Kai Cao Huaizhou Wang Shizheng Wu Qiang Zhu Guozhong Wang Tianyi Wu Ningli Wang Beijing Tongren eye Center Beijing Tongren HospitalCapital Medical UniversityBeijing Ophthalmology and Visual Sciences Key LaboratoryBeijing100730China Beijing institute of Ophthalmology Beijing Tongren HospitalCapital Medical UniversityBeijing100005China The Viterbi Family Department of Ophthalmology Shiley Eye InstituteUniversity of CaliforniaSan DiegoCA92121USA Department of Ophthalmology University of CaliforniaSan FranciscoCA94143USA Institution of Geriatric Qinghai Provincial Hospital Xining810007China Department of Ultrasound Beijing Tongren HospitalCapital Medical UniversityBeijing100730China Department of Hyperbaric and Hypobaric Chamber Civil Aviation General HospitalBeijing100025China National Key Laboratory of High Altitude medicine China High Altitude Medical Research InstituteXining810012China

Increased cerebral blood flow resulting from altered capillary level autoregulation at high altitudes leads to capillary overperfusion and then vasogenic cerebral edema,which is the leading hypothesis of acute mountain sickness(AMS).However,studies on cerebral blood flow in AMS have been mostly restricted to gross cerebrovascular endpoints as opposed to the *** study aimed to investigate ocular microcirculation alterations,the only visualized capillaries in the central neural system(CNS),during early-stage AMS using a hypobaric *** study found that after high altitude simulation,the optic nerve showed retinal nerve fiber layer thickening(P=0.004–0.018)in some locations,and the area of the optic nerve subarachnoid space(P=0.004)*** coherence tomography angiography(OCTA)showed increased retinal radial peripapillary capillary(RPC)flow density(P=0.003–0.046),particularly on the nasal side of the *** AMSpositive group had the largest increases in RPC flow density in the nasal sector(AMS-positive,?3.21±2.37;AMS-negative,?0.01±2.16,P=0.004).Among multiple ocular changes,OCTA increase in RPC flow density was associated with simulated early-stage AMS symptoms(beta=0.222,95%CI,0.009–0.435,P=0.042).The area under the receiver operating characteristics curve(AUC)for the changes in RPC flow density to predict early-stage AMS outcomes was 0.882(95%CI,0.746–0.998).The results further confirmed that overperfusion of microvascular beds is the key pathophysiologic change in early-stage *** OCTA endpoints may serve as a rapid,noninvasive potential biomarker for CNS microvascular changes and AMS development during risk assessment of individuals at high altitudes.

关键词： optical coherence tomography angiography retinal microvasculature acute mountain sickness

Future Science Prize goes to non-invasive prenatal testing

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Science China(Life Sciences) 2017年第4期60卷 429-431页

作者： Kang Li Yaou Duan Magdalene Yin Lin Ting Zhiying Ou Li Liu Kang Zhang Xin Fu Molecular medicine Research Center Department of Ophthalmology West China Hospital Sichuan University Sichuan 610041 China Guangzhou Elite Health Biological Pharmaceutical Technology Company Ltd. Guangzhou 510005 China institute for genomic medicine and shiley eye institute University of California San Diego La JoUa CA 92328 USA Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou 510623 China

The Future Forum,a non-profit organization established last year in Beijing,announced that pathologist Dennis Ming Yuk Lo from the Chinese University of Hong Kong won the life sciences Future Science Prize for the discovery of fetal cell-free DNA(cfDNA)in maternal plasma in 1997(Lo et al.,1997).By detecting male fetus-derived Y sequences in maternal plasma,Lo et *** proved the presence of fetal cfDNA in maternal plasma and serum(Lo et al.,1997).This discovery has opened up a tremendous breadth of

关键词： Future Science Prize goes to non-invasive prenatal testing

Identification of novel loci influencing refractive error in East Asian populations using an extreme phenotype design

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Journal of Genetics and genomics 2022年第1期49卷 54-62页

作者： Xiaotong Han Tianzi Liu Xiaohu Ding Jialin Liu Xingyan Lin Decai Wang Moeen Riaz Paul N.Baird Zhi Xie Yuan Cheng Yi Li Yuki Mori Masahiro Miyake Hengtong Li Ching-Yu Cheng Changqing Zeng Kyoko Ohno-Matsui Xiangtian Zhou Fan Liu Mingguang He State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhou 510000China CAS Key Laboratory of genomic and Precision medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Beijing 100101China University of Chinese Academy of Sciences Beijing 100101China School of Public Health and Preventive medicine Monash UniversityMelbourne 3800Australia Department of Surgery OphthalmologyFaculty of MedicineDentistry and Health SciencesThe University of MelbourneMelbourneVictoria 3010Australia Department of Ophthalmology and Visual Science Tokyo Medical and Dental UniversityTokyo 113-8510Japan Singapore eye Research institute Singapore National Eye Centre 168751Singapore Department of Ophthalmology Yong Loo Lin School of MedicineNational University of Singapore 119077Singapore Centre for Quantitative medicine Duke-NUS Medical School 169857Singapore School of Optometry and Ophthalmology and eye Hospital Wenzhou Medical UniversityWenzhouZhejiang 325035China State Key Laboratory of Optometry Ophthalmology and Vision ScienceWenzhouZhejiang 325035China

The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies(GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent(SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou(631 0.00 D) and Wenzhou(593 -1.75 D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci, which show genome-wide significant associations with SE, including 1 q25.2 FAM163 A, 10 p11.22 NRP1/PRAD3, and 10 p11.21 ANKRD30 A/MTRNR2 L7, together explaining 3.34% of SE variance. 10 p11.21 is successfully *** allele frequencies of all three loci show significant differences between major continental groups(P < 0.001). The SE reducing(more myopic) allele of rs10913877(1 q25.2 FAM163 A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans(EAS = 0.60,EUR = 0.20, and AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5, and ARPP19. These results provide new insights into myopia pathogenesis and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.

关键词： Extreme phenotype Genome-wide association study Population heterogeneity Refractive error East Asian population Prediction

A proposal:a comprehensive platform to characterize tumors in Chinese and improve success in cancer drug discovery and development

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Chinese Journal of Cancer 2011年第6期30卷 363-367页

作者： Pearl S. Huang Peter T. Ho Kang Zhang Beigene Ltd. Beijing 102206 P. R. China Molecular medicine Center West China Hospital Sichuan University Chengdu SJchuan 610041 P. R. China institute for genomic medicine and shiley eye Center University of California at San Diego La Jolla CA 92093 USA.

Cancer is a collection of complex diseases in which cell proliferation and apoptosis are dysregulated due to the acquisition of genetic changes in cancer *** genetic changes,combined with the interrelated physiologic adaptations of neo-angiogenesis,recruitment of stromal support tissues,and suppression of immune recognition,are measurable characteristics in tumor gene expression profiles and biochemical *** measures can lead to identification of disease drivers and,ultimately,can be used to assign *** advances in RNA sequencing technologies,the ability to simultaneously measure all genetic and gene expression changes with a single technology is now *** ability to create a comprehensive catalog of genotypic and phenotypic changes in a collection of histologically similar but otherwise distinct tumors should allow for a more precise positioning of existing targeted therapies and identification of new targets for intervention.

关键词：药物发现肿瘤基因表达谱开发抗癌中国平台基因变化

Molecular mechanisms of the suppression of axon regeneration by KLF transcription factors

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Neural Regeneration Research 2014年第15期9卷 1418-1421页

作者： Akintomide Apara Jeffrey L.Goldberg University of Miami Miller School of medicine MiamiFL USA shiley eye CenterUniversity of California San Diego La JollaCA USA

Molecular mechanisms of the Kruppel-like family of transcription factors （KLFs） have been studied more in proliferating cells than in post-mitotic cells such as neurons. We recently found that KLFs regulate intrinsic axon growth ability in central nervous system （CNS） neurons in- cluding retinal ganglion cells, and hippocampal and cortical neurons. With at least 15 of 17 KLF family members expressed in neurons and at least 5 structurally unique subfamilies, it is import- ant to determine how this complex family functions in neurons to regulate the intricate genetic programs of axon growth and regeneration. By characterizing the molecular mechanisms of the KLF family in the nervous system, including binding partners and gene targets, and comparing them to defined mechanisms defined outside the nervous system, we may better understand how KLFs regulate neurite growth and axon regeneration.

关键词： optic nerve regeneration axon growth retina retinal ganglion cells spinal cord transcription factors

genomic instability and eye diseases

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Advances in Ophthalmology Practice and Research 2023年第3期3卷 103-111页

作者： Hongyan Liu Jun Cheng Xiaoyun Zhuang Benxiang Qi Fenfen Li Bining Zhang eye institute of Shandong First Medical University Qingdao Eye Hospital of Shandong First Medical UniversityQingdaoChina School of Ophthalmology Shandong First Medical UniversityQingdaoChina State Key Laboratory Cultivation Base Shandong Provincial Key Laboratory of OphthalmologyQingdaoChina eye institute of Shandong First Medical University Eye Hospital of Shandong First Medical University(Shandong Eye Hospital)JinanChina Department of Ophthalmology School of Clinical MedicineWeifang Medical UniversityWeifangChina The eye Hospital of Wenzhou Medical University HangzhouChina

Background:Genetic information is stored in the bases of double-stranded ***,the integrity of DNA molecules is constantly threatened by various mutagenic agents,including pollutants,ultraviolet light(UV),and *** counteract these environmental damages,cells have established multiple mechanisms,such as producing molecules to identify and eliminate damaged DNA,as well as reconstruct the original DNA *** or insufficiency of these mechanisms can cause genetic ***,the role of genome stability in eye diseases is still under-researched,despite extensive study in cancer *** text:As the eye is directly exposed to the external environment,the genetic materials of ocular cells are constantly under *** of the proteins essential for DNA damage repair,such as pRb,p53,and RAD21,are also key during the ocular disease *** this review,we discuss five ocular diseases that are associated with genomic *** and pterygium are linked to abnormal cell ***’corneal endothelial dystrophy and age-related macular degeneration are related to the accumulation of DNA damage caused by oxidative damage and *** mutation of the subunit of the cohesin complex during eye development is linked to ***:Failure of DNA damage detection or repair leads to increased genomic *** the role of genomic instability in ocular diseases can lead to the development of new treatments and strategies,such as protecting vulnerable cells from risk factors or intensifying damage to unwanted cells.

关键词： genomic instability Ocular diseases Retinoblastoma Cornea Pterygium