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High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes

Bone Research 2014年第3期2卷 152-181页

作者： Robert Brommage Jeff Liu gwenn M Hansen Laura L Kirkpatrick david g potter.ar.hur.t ss Brian Zambrowicz david R Powell Peter Vogel Lexicon Pharmaceuticals The Woodlands TX USA

Screening gene function in vivo is a powerful approach to discover novel drug targets. We present high-throughput screening （HtS） data for 3 762 distinct global gene knockout （KO） mouse lines with viable adult homozygous mice generated using either gene-trap or homologous recombination technologies. Bone mass was determined from DEXA scans of male and female mice at 14 weeks of age and by microCt analyses of bones from male mice at 16 weeks of age. Wild-type （Wt） cagemates/littermates were examined for each gene KO. Lethality was observed in an additional 850 KO lines. Since primary HtS are susceptible to false positive findings, additional cohorts of mice from KO lines with intriguing HtS bone data were examined. Aging, ovariectomy, histomorphometry and bone strength studies were performed and possible non-skeletal phenotypes were explored. together, these screens identified multiple genes affecting bone mass： 23 previously reported genes （Calcr, Cebpb, Crtap, Dcstamp, Dkkl, Duoxa2, Enppl, Fgf23, Kissl/Kisslr, Kl （Klotho）, Lrp5, Mstn, Neol, Npr2, Ostml, Postn, Sfrp4, S1c30a5, Sic39a13, Sost, Sumf1, Src, Wnt10b）, five novel genes extensively characterized （Cldn18, Fam20c, Lrrkl, Sgpll, Wnt16）, five novel genes with preliminary characterization （Agpat2, RassfS, Slc10a7, Stc26a7, Slc30a10） and three novel undisclosed genes coding for potential osteoporosis drug targets.

关键词： KO High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes BMD HtS DEXA gene

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World Journal of gastroenterology 2014年第14期20卷 3986-4000页

作者： Bjarte Fosby Sigrid Nss Johannes R Hov James traherne Kirsten M Boberg John trowsdale Aksel Foss Pl-Dag Line Andre Franke Espen Melum Helge Scott tom H Karlsen Norwegian PSC Research Center Division of CancerSurgery and TransplantationOslo University Hospital Institute of Clinical Medicine Faculty of MedicineUniversity of Oslo Kg Jebsen Inflammation Research Centre Research Institute of Internal MedicineOslo University Hospital Department of transplantation Medicine Division of CancerSurgery and TransplantationOslo University Hospital Division of Immunology Department of PathologyUniversity of Cambridge and Cambridge Institute for Medical ResearchUniversity of Cambridge Institute of Clinical Molecular Biology Christian-Albrechts-University Department of Pathology Divisoin of Diagnostics and InterventionInstitute of PathologyOslo University Hospital

AIM: to investigate influence of human leukocyte antigen (HLA) and killer immunoglobuline-like receptor (KIR) genotypes on risks of acute rejection (ar) after liver transplantation (LtX).

关键词： Liver transplantation Primary sclerosing cholangitis Acute rejection Human leukocyte antigen Killer immunoglobulin-like receptor

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Osteocyte Egln1/Phd2 links oxygen sensing and biomineralization via FgF23

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Bone Research 2023年第1期11卷 178-192页

作者： Megan L.Noonan Pu Ni Emmanuel Solis Yamil g.Marambio Rafiou Agoro Xiaona Chu Yue Wang Hongyu gao Xiaoling Xuei Erica L.Clinkenbeard guanglong Jiang Sheng Liu Steve Stegen geert Carmeliet William R.thompson Yunlong Liu Jun Wan Kenneth E.White Department of Medical and Molecular genetics Indiana University School of MedicineIndianapolisIN46202USA Laboratory of Clinical and Experimental Endocrinology Department of Chronic Diseases and MetabolismKU Leuven3000LeuvenBelgium Department of Physical therapy Indiana University School of MedicineIndianapolisIN46202USA Department of Anatomy Cell Biologyand PhysiologyIndiana University School of MedicineIndianapolisIN46202USA Center for Computational Biology and Bioinformatics Indiana University School of MedicineIndianapolisIN46202USA Departments of Medicine/Division of Nephrology Indiana University School of MedicineIndianapolisIN46202USA

Osteocytes act within a hypoxic environment to control key steps in bone ***23,a critical phosphate-regulating hormone,is stimulated by low oxygen/iron in acute and chronic diseases,however the molecular mechanisms directing this process remain *** goal was to identify the osteocyte factors responsible for FgF23 production driven by changes in oxygen/iron ***-inducible factor-prolyl hydroxylase inhibitors(HIF-PHI)which stabilize HIF transcription factors,increased Fgf23 in normal mice,as well as in osteocyte-like cells;in mice with conditional osteocyte Fgf23 deletion,circulating i FgF23 was *** inducible MSC cell line(‘MPC2’)underwent Fg-4592 treatment and AtACseq/RNAseq,and demonstrated that differentiated osteocytes significantly increased HIF genomic accessibility versus progenitor *** genomics also revealed increased prolyl hydroxylase Egln1(Phd2)chromatin accessibility and expression,which was positively associated with osteocyte *** mice with chronic kidney disease(CKD),Phd1-3 enzymes were suppressed,consistent with FgF23 upregulation in this *** loss of Phd2 from osteocytes in vivo resulted in upregulated Fgf23,in line with our findings that the MPC2 cell line lacking Phd2(CRISPR Phd2-KO cells)constitutively activated Fgf23 that was abolished by HIF1α*** vitro,Phd2-KO cells lost iron-mediated suppression of Fgf23 and this activity was not compensated for by Phd1 *** sum,osteocytes become adapted to oxygen/iron sensing during differentiation and are directly sensitive to bioavailable ***,Phd2 is a critical mediator of osteocyte FgF23 production,thus our collective studies may provide new therapeutic targets for skeletal diseases involving disturbed oxygen/iron sensing.

关键词： FgF23 collective adapted

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