Richard Davis

Personal Information
Title Professor
Expertise All Complications
Institution University of California Los Angeles
Data Summary
Grants/SubContracts 2
Progress Reports 6
Presentations 2
Publications 13
Protocols 0
Committees 0
Experiments 0
Strains 1
Models 0

Atherosclerosis /other complications in hyperlipidemic BKS diabetic mouse
Grant Number: HL087944

Abstract: Diabetes, and the complications of diabetes, are the result of complex genetic and environmental interactions. In the present cycle of the AMDCC, we have sought to identify realistic animal models of the complications of diabetes by characterizing naturally occurring variations among inbred strains of mice that impact diabetes, insulin resistance and athersclerosis. Among the most promising models is the classic BKS.db mouse. BKS.db consists of a combination of alleles derived from inbred strain DBA on the background of strain C57BL/6, along with a null mutation of the leptin recepter gene db. During the present AMDCC cycle we identified all of the regions of BKS that are derived from DBA using very high density SNP mapping. These regions are scattered throughout the genome, and it is clear that multiple DBA alleles are required for the development of diabetes and its complications. We then identified two strong candidates for the DBA alleles required for diabetes: 5-lipoxygenase (5LO) and lipin, both of which are dramatically reduced in activity in BKS as compared to C57BL/6. In this application we will extend the investigations of 5LO, lipin and other genes predisposing to diabetes and its complications in BKS.db. We will also introduce the apolipoprotein E (Apo E) null mutation onto BKS to produce a model for diabetes - induced athersclerosis. To facilitate the genetic dissection of this model we have produced a whole genome set of congenic strains in which regions of DBA have been introgressed on the background of C57BL/6. Our analyses will incorporate state of the art physiologic and bioinformatic approaches and will integrate an expression quantitative trait locus (eQTL) database that we have developed over the past several years.

Institution: University of California Los Angeles
100 Stein Plz
Los Angeles, CA
Fiscal Year:2006
Project Start: 9/4/2006
Project End: 8/31/2011


The Animal Model of Diabetic Complications Consortium Pilot & Feasibility (P&F)
Complex diseases such as diabetes and its complications are, most commonly, the result of many small gene variations, no one of which is responsible for a major portion of disease susceptibility. Recently, we have developed strategies to identify modules of co-expressed genes in that are strongly associated with disease phenotypes and which account for a major portion of phenotypic variation. As such, these network modules constitute promising new models of disease both as diagnostic criteria and as therapeutic targets. We have generated and characterized a large F2 intercross between strains BLKS and B6 on the background of the db/db mutation. Preliminary data indicate significant variations in heart and kidney pathology. To Identify the underlying genes for cardiomyopathy and nephropathy, we will perform expression array profiling of the kidneys and hearts of a subset of the F2 mice and identify transcripts whose levels correlate with clinical phenotypes (tissue histology, excreted albumin and creatinine, blood urea nitrogen, plasma creatinine, obesity, insulin levels, lipoprotein levels, blood pressure) and whose levels are regulated by quantitative trait loci (QTL) for nephropathy and cardiomyopathy. We hypothesize that we will identify genes whose expression correlates strongly with the clinical traits and whose levels are determined by clinical trait QTL. Further, we will construct gene co-expression networks and will identify modules within these networks that are associated with diabetes and its complications. We hypothesize that we will identify gene networks strongly correlated with nephropathy and cardiomyopathy that will help identify pathologic pathways and mechanisms. We will correlate these diabetes- and complication-specific modules with expression differences seen between resistant B6 db/db mice and susceptible BLKS db/db mice. Ultimately, understanding of complication-specific expression modules, will provide diagnostic models for disease susceptibility and model targets for therapeutic interventions. Given the conservation of modules we observe across species, these results will be powerful in informing diagnosis, treatment and prevention of human disease.

Progress Reports

Annual Reports

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Title YearTypeOptions
Davis, Richard (2007)
2007Annual Report
Davis, Richard (2008)
2008Annual Report
Davis, Richard (2009)
2009Annual Report
Davis, Richard (2010)
2010Annual Report
Davis, Richard (2011)
2011Annual Report

 PublicationAltmetricsSubmitted ByPubMed IDStatus

Year: 2014; Items: 1

Genetic modulation of diabetic nephropathy among mouse strains with Ins2 Akita mutation.
Wu X, Davis RC, McMillen TS, Schaeffer V, Zhou Z, Qi H, Mazandarani PN, Alialy R, Hudkins KL, Lusis AJ, LeBoeuf RC
Physiological reports, 2014 (2)
Submitted Externally

Year: 2012; Items: 2

A systems genetic analysis of high density lipoprotein metabolism and network preservation across mouse models.
Langfelder P, Castellani LW, Zhou Z, Paul E, Davis R, Schadt EE, Lusis AJ, Horvath S, Mehrabian M
Biochimica et biophysica acta, 2012 (1821), 435 - 447
Submitted Externally
Insulin clearance: confirmation as a highly heritable trait, and genome-wide linkage analysis.
Guo X, Cui J, Jones MR, Haritunians T, Xiang AH, Chen YD, Taylor KD, Buchanan TA, Davis RC, Hsueh WA, Raffel LJ, Rotter JI, Goodarzi MO
Diabetologia, 2012 (55), 2183 - 2192

Year: 2010; Items: 1

Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice.
Davis RC, Castellani LW, Hosseini M, Ben-Zeev O, Mao HZ, Weinstein MM, Jung DY, Jun JY, Kim JK, Lusis AJ, Péterfy M
Diabetes, 2010 (59), 1616 - 1625

Year: 2009; Items: 1

Maternal low-protein diet or hypercholesterolemia reduces circulating essential amino acids and leads to intrauterine growth restriction.
Bhasin KK, van Nas A, Martin LJ, Davis RC, Devaskar SU, Lusis AJ
Diabetes, 2009 (58), 559 - 566

Year: 2008; Items: 1

Association of insulin sensitivity and glucose tolerance with the c.825C>T variant of the G protein beta-3 subunit gene.
Kopf D, Cheng LS, Blandau P, Hsueh W, Raffel LJ, Buchanan TA, Xiang AH, Davis RC, Rotter JI, Lehnert H
Journal of diabetes and its complications, 2008 (22), 205 - 209

Year: 2007; Items: 3

Recipes for Creating Animal Models of Diabetic Cardiovascular Disease
Willa Hsueh, E. Dale Abel, Jan L. Breslow, Nobuyo Maeda, Richard C. Davis, Edward A. Fisher, Hayes Dansky, Donald A. McClain, Richard McIndoe, Momtaz K. Wassef, Cristina Rabadan-Diehl, Ira J. Goldberg
Circulation research, 2007 (100), 1415 - 1427
A genome-wide set of congenic mouse strains derived from CAST/Ei on a C57BL/6 background.
Davis RC, Jin A, Rosales M, Yu S, Xia X, Ranola K, Schadt EE, Lusis AJ
Genomics, 2007 (90(3)), 306 - 313
Metabolic syndrome as a modifier of atherosclerosis in murine models.
Péterfy M, Davis RC, Lusis AJ
Current drug targets, 2007 (8(11)), 1215 - 1220

Year: 2006; Items: 1

Impact of chromosome 2 obesity loci on cardiovascular complications of insulin resistance in LDL receptor-deficient C57BL/6 mice.
Estrada-Smith D, Collins AR, Wang X, Crockett C, Castellani L, Lusis AJ, Davis RC
Diabetes, 2006 (55(8)), 2265 - 2271

Year: 2005; Items: 3

A genome-wide set of congenic mouse strains derived from DBA/2J on a C57BL/6J background.
Davis RC, Schadt EE, Smith DJ, Hsieh EW, Cervino AC, van Nas A, Rosales M, Doss S, Meng H, Allayee H, Lusis AJ
Genomics, 2005 (86(3)), 259 - 270
Integrating genetic and gene expression data to study the metabolic syndrome and diabetes in mice.
Drake TA, Schadt EE, Davis RC, Lusis AJ
American journal of therapeutics, 2005 (12(6)), 503 - 511

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Title YearTypeOptions
Davis, Richard (2007)
Davis, Richard (2009)

No protocols found.

No committees found.

No experiments found.

No models found.