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| 1 | High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes显示文摘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, Dkk1, Duoxa2, Enpp1, Fgf23, Kiss1/Kiss1 r, Kl(Klotho),Lrp5, Mstn, Neo1, Npr2, Ostm1, Postn, Sfrp4, Slc30a5, Slc39a13, Sost, Sumf1, Src, Wnt10b), five novel genes extensively characterized(Cldn18, Fam20 c, Lrrk1, Sgpl1, Wnt16), five novel genes with preliminary characterization(Agpat2, Rassf5, Slc10a7, Slc26a7, Slc30a10) and three novel undisclosed genes coding for potential osteoporosis drug targets. | Robert Brommage Jeff Liu Gwenn M Hansen Laura L Kirkpatrick David G Potter Arthur T Ss Brian Zambrowicz David R Powell Peter Vogel | 2014 | Bone Research2014，2，3： | 7 |
| 2 | The Tryptophan Hydroxylase Inhibitor LX1031 Shows Clinical Benefit in Patients With Nonconstipating Irritable Bowel Syndrome显示文摘 | Philip M. Brown Douglas A. Drossman Alastair J.J. Wood Gary A. Cline Kenny S. Frazier Jessica I. Jackson Johanna Bronner Joel Freiman Brian Zambrowicz Arthur Sands Michael D. Gershon | 2011 | Gastroenterology2011，，2： | 2 |
| 3 | NOTUM inhibition increases endocortical bone formation and bone strength显示文摘The disability,mortality and costs caused by non-vertebral osteoporotic fractures are enormous.Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures.Cortical bone is a major determinant of non-vertebral bone strength.To identify novel osteoporosis drug targets,we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes.Cortical bone thickness was substantially elevated in Notum?/?mice.NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts.Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed.They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation.Thus,inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures. | Robert Brommage Jeff Liu Peter Voge Faika Mseeh Andrea Y.Thompson David G.Potter Melanie K.Shadoan Gwenn M.Hansen Sabrina Jeter-Jones Jie Cui Dawn Bright Jennifer P.Bardenhagen Deon D.Doree Sofia Moverare-Skrtic Karin H.Nilsson Petra Henning Ulf H.Lerner Claes Ohlsson Arthur T.Sands James E.Tarver David R.Powell Brian Zambrowicz Qingyun Liu | 2019 | Bone Research2019，7，1： | 2 |
| 4 | LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial 显示文摘 | Zambrowicz B Freiman J Brown P M | 2012 | Clin Pharmacol Ther2012，92，2： | 1 |
| 5 | Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells 显示文摘 | Zambrowicz BP Imamoto A Fiering S | 1997 | Proc Natl Acad Sci USA1997，94，8： | 1 |
| 6 | Tissue nonspecific alkaline phosphatase is expressed in both embryonic and extraembryonic lineages during mouse embryogenesis but is not required for migration of primordial germ cells显示文摘 | MacGregor GR Zambrowicz BP Soriano P | 1995 | Development1995，121，5： | 1 |
| 7 | Tissue non- specific alkaline phospatase is expressed in both embryonic and extraembryonic lineages during mouse embryogenesis but is not required for migration of primordial germ cells显示文摘 | Macgregor G R Zambrowicz B P Soriano P | 1995 | Devel- opment1995，121，5： | 1 |
| 8 | Effects of LX4211, a dual sodium-dependent glucose cotransporters 1 and 2 inhibitor, on postprandial glucose, insulin, glucagon-like peptide 1, and peptide tyrosine tyrosine in a dose-timing study in healthy subjects 显示文摘 | Zambrowicz B Ogbaa I Frazier K | 2013 | Clin ther2013，35，8： | 1 |
| 9 | Effects of LX4211, a dual SGLT1/SGLT2 inhibitor, plus sitagliptin on postprandial active GLP-1 and glycemic control in type 2 diabetes 显示文摘 | Zambrowicz B Ding Z M Ogbaa I | 2013 | Clin Ther2013，35，3： | 1 |
| 10 | LX4211 reduces postprandial glucose in patients with type 2 diabetes mellitus and renal impairment despite low urinary glucose excretion 显示文摘 | Zambrowicz B Lapuerta P Strumph P | 2015 | Clin Ther2015，37，1： | 1 |
| 11 | Gene trap mutagenesis显示文摘 | Abuin A Hansen GM Zambrowicz B | 2007 | Handb Exp Pharmacol2007，178，： | 1 |
| 12 | Modeling drug action in the mouse with knockouts and RNA interference 显示文摘 | ZAMBROWICZ BP SANDS AT | 2004 | Drug Discov Today: Targets2004，3，5： | 1 |
| 13 | LX4211,a dual SGLT1/SGLT2 inhibitor,improved glycemic control in patients with type 2 diabetes in a randomized,placebocontrolled trial显示文摘 | Zambrowicz B Freiman J Brown PM | 2012 | Clin Pharmacol Ther2012，92，2： | 1 |
| 14 | Effects of LX4211,a dual sodium-dependent glucose cotransporters 1 and 2 inhibitor,on postprandial glucose,insulin,glucagon-like peptide1,and peptide tyrosine tyrosine in a dose-timing study in healthy subjects显示文摘 | Zambrowicz B Ogbaa I Frazier K | 2013 | Clin Ther2013，35，8： | 1 |
| 15 | Knockouts model the 100 bestselling drugs--will they model the next 100显示文摘 | Zambrowicz BP Sands AT | | 0，，01： | 1 |
| 16 | Effects of LX4211,a dual SGLT1/SGLT2 inhibitor,plus sitagliptin on postprandial active GLP-1 and glycemic control in type 2 diabetes显示文摘 | Zambrowicz B Ding ZM Ogbaa I | 2013 | Clin Ther2013，35，3： | 1 |
| 17 | Development of sotagliflozin,a dual sodium-dependent glucose transporter1/2 inhibitor显示文摘 | Lapuerta P Zambrowicz B Strumph P | 2015 | Diab Vasc Dis Res2015，12，2： | 1 |
| 18 | Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes显示文摘 | Sands Arthur T Zambrowicz Brian P Rosenstock Julio Lapuerta Pablo Bode Bruce W Garg Satish K Buse John B Banks Phillip Heptulla Rubina Rendell Marc Cefalu William T Strumph Paul | 2015 | Diabetes Care2015，，7： | 1 |
| 19 | LX4211, a Dual SGLT1/SG LT2 Inhibitor, Improved Glycemic Control in Patients WithType 2 Diabetes in a Randomized, Placebo-Controlled Trial显示文摘 | B Zambrowicz J Freiman PM Brown | 2012 | Clini-cal trial2012，92，2： | 1 |
| 20 | LX4211,a dual inhibitor of sodium glucose transporters SGLT1 and SGLT2,reduces blood pressure in patients with type 2 diabetes显示文摘 | Lapuerta P Neutel J Zambrowicz B | 2013 | Diabetologia2013，56，1： | 1 |
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