Member Profile
Richard Davis
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 |
|---|
| Department: | MEDICINE |
|---|
| Project Start: | 9/4/2006 |
|---|
| Project End: | 8/31/2011 |
|---|
| ICD: | NATIONAL HEART, LUNG, AND BLOOD INSTITUTE |
|---|
|
|
SubContract(s)
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.
|
| Status |
| | 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 | 25428948 | Published |
| | 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 | 21807117 | Published |
| | 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 |
| | 22584727 | Published |
| | 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 |
| | 20393148 | Published |
| | |
| | 19073773 | Published |
| | 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 |
| | 18413224 | Published |
| | Recipes for Creating Animal Models of Diabetic Cardiovascular DiseaseWilla 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 |
| | 17525381 | Published |
| | |
| | 17600671 | Published |
| | |
| | 18045100 | Published |
| | |
| | 16873689 | Published |
| | |
| | 15793261 | Published |
| | 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 |
| | 16039824 | Published |
| | |
| | 16280644 | Published |
|
|
Welcome to the DiaComp Login / Account Request Page.
|
|
Not a member?
If you are a funded DiaComp investigator, a member of an investigator's lab,
or an external advisor to the consortium, please
request an account.
Forgot your password?
|
ERROR!
There was a problem with the page: