The overall objective is to identify-the loci which cause genetic differences in blood pressure in the rat. Because hypertension in animals and humans is a complex polygenic disease it can best be understood genetically in animals where controlled breeding is possible. We have focused our genetic studies on candidate genes in the inbred Dahl salt-hypertension sensitive (S) and inbred Dahl salt-hypertension resistant (R) rats. Genetic polymorphisms are sought at the DNA level in or near genetic loci thought (on the basis of their known biochemical/ physiological actions) to be relevant to blood pressure regulation. It is determined if a component of blood pressure and genotypes at the candidate locus cosegregate in populations derived from crosses of S and R, or S and other contrasting """"""""control"""""""" strains. If so, this establishes the candidate locus (or an unknown closely linked locus) as a cause for genetic differences in blood pressure. DNA sequence analysis of the candidate alleles involved is then required to find a structural difference that is likely to have functional consequences with regard to blood pressure. If cosegregation is negative the candidate locus can be rejected as causing blood pressure differences provided the experiments have adequate statistical power and several different populations are studied. For candidate loci which cosegregate with blood pressure, the result will be con-firmed by the production of congenic strains. The low blood pressure allele from a control strain is transferred to the S genetic background by the standard genetic technique of repeated backcrossing to S with counter selection for the low blood pressure allele. The congenic S strain should have lower blood pressure than the parental S strain if in fact the allele transferred lowers blood pressure. """"""""Double congenic"""""""" strains will be produced by crossing two single congenics each of which carries genes for low blood pressure at different loci on the S genetic background. Comparisons of blood pressure among double and single congenics with the parental S strain will allow definition of interactions between the loci involved. Initial studies show that such interactions are required for really high levels of genetically regulated blood pressure to be achieved. It is likely that understanding such complexity requires animal breeding techniques, and cannot be initially unraveled in work with humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL020176-19
Application #
2215326
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1988-06-01
Project End
1998-05-31
Budget Start
1995-06-01
Budget End
1996-05-31
Support Year
19
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Toledo
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Waghulde, Harshal; Cheng, Xi; Galla, Sarah et al. (2018) Attenuation of Microbiotal Dysbiosis and Hypertension in a CRISPR/Cas9 Gene Ablation Rat Model of GPER1. Hypertension 72:1125-1132
Galla, Sarah; Chakraborty, Saroj; Mell, Blair et al. (2017) Microbiotal-Host Interactions and Hypertension. Physiology (Bethesda) 32:224-233
Haller, Steven T; Kumarasamy, Sivarajan; Folt, David A et al. (2017) Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure. Kidney Int 91:365-374
Kumarasamy, Sivarajan; Solanki, Sumeet; Atolagbe, Oluwatomisin T et al. (2017) Deep Transcriptomic Profiling of M1 Macrophages Lacking Trpc3. Sci Rep 7:39867
Cheng, Xi; Waghulde, Harshal; Mell, Blair et al. (2016) Pleiotropic Effect of a High Resolution Mapped Blood Pressure QTL on Tumorigenesis. PLoS One 11:e0153519
Gopalakrishnan, Kathirvel; Kumarasamy, Sivarajan; Mell, Blair et al. (2015) Genome-wide identification of long noncoding RNAs in rat models of cardiovascular and renal disease. Hypertension 65:200-10
Mehta, Gaurav; Kumarasamy, Sivarajan; Wu, Jian et al. (2015) MITF interacts with the SWI/SNF subunit, BRG1, to promote GATA4 expression in cardiac hypertrophy. J Mol Cell Cardiol 88:101-10
Kumarasamy, Sivarajan; Waghulde, Harshal; Gopalakrishnan, Kathirvel et al. (2015) Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension. Nat Commun 6:6252
Mell, Blair; Abdul-Majeed, Shakila; Kumarasamy, Sivarajan et al. (2015) Multiple blood pressure loci with opposing blood pressure effects on rat chromosome 1 in a homologous region linked to hypertension on human chromosome 15. Hypertens Res 38:61-7
Joe, Bina (2015) Dr Lewis Kitchener Dahl, the Dahl rats, and the ""inconvenient truth"" about the genetics of hypertension. Hypertension 65:963-9

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