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 #
5R37HL020176-26
Application #
6536767
Study Section
Special Emphasis Panel (NSS)
Program Officer
Barouch, Winifred
Project Start
1988-06-01
Project End
2004-02-22
Budget Start
2002-06-01
Budget End
2004-02-22
Support Year
26
Fiscal Year
2002
Total Cost
$535,533
Indirect Cost
Name
University of Toledo
Department
Physiology
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
Joe, Bina (2015) Dr Lewis Kitchener Dahl, the Dahl rats, and the ""inconvenient truth"" about the genetics of hypertension. Hypertension 65:963-9
Mell, Blair; Jala, Venkatakrishna R; Mathew, Anna V et al. (2015) Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol Genomics 47:187-97
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

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