Our long-term goal is to identify genes pre-disposing animals to blood pressure salt-sensitivity or salt-resistance, with the eventual goal of applying this knowledge to elucidating factors influencing blood pressure in humans. We previously identified two loci on rat chromosome 3 (RNO3) linked to blood pressure in a segregating population bred from inbred Dahl salt-sensitive (S) and salt-resistant (R) rats. One of these blood pressure (BP) quantitative trait loci (QTL), located near the q-terminus of RNO3, was confirmed by developing a congenic strain, S.R-Edn3. Congenic substrains derived from S.R-Edn3 indicated that at least two distinct BP QTLs are present at the q-terminus of RNO3 and delimited the QTL-containing region to 3.3 cM interval. We propose to better define this QTL-containing interval's extent, which will assist in identifying gene(s) responsible for this BP QTL. We hypothesize that these are at least three distinct BP/cardiac mass QTLs present on RNO3 and that the S.R-Edn3 congenic rat carries low BP alleles for two distinct RNO3 BP QTL and that differences in the expression of R-rat derived gene(s) in this region are responsible, in part, for this congenic strain's observed decreased blood pressure.
Our SPECIFIC AIMS are to: 1) develop congenic substrains derived from S.R-Edn3, that carry the BP QTLs in smaller portions of the R-rat derived RNO3 and eventually narrowing this region to 1.0 cM; 2) develop congenic strains """"""""trapping"""""""" the third BP QTL present on RNO3 near D3Wox3, which maps over 90 cM away from the two BP QTL located near the q-terminus. This region of R-rat chromosome will be introgressed into the S strain. 3) develop detailed genetic, comparative, and physical maps of the RNO3 region containing the BP QTL identified in SPECIFIC AIM 1 using contigs of bacterial artificial chromosomes (BAC) and P1 artificial chromosomes (PAC); 4) identify strong candidate genes for the RNO3 BP QTL, and genes located within the QTL-containing regions will be evaluated as candidates. We will also identify genes differentially-expressed in congenic substrains, compared with the parental S strain, by using the cDNA array hybridization technique. Differentially-expressed genes that map in the QTL-containing region (identified in SPECIFIC AIM 1) will be superior candidate genes for that specific blood pressure QTL.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068994-04
Application #
6970869
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lin, Michael
Project Start
2002-12-16
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2007-11-30
Support Year
4
Fiscal Year
2006
Total Cost
$287,091
Indirect Cost
Name
University of Toledo
Department
Physiology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Nestor Kalinoski, Andrea L; Ramdath, Ramona S; Langenderfer, Kay M et al. (2010) Neointimal hyperplasia and vasoreactivity are controlled by genetic elements on rat chromosome 3. Hypertension 55:555-61
Cicila, George T; Morgan, Eric E; Lee, Soon Jin et al. (2009) Epistatic genetic determinants of blood pressure and mortality in a salt-sensitive hypertension model. Hypertension 53:725-32
Lee, Soon Jin; Liu, Jun; Westcott, Allison M et al. (2006) Substitution mapping in dahl rats identifies two distinct blood pressure quantitative trait loci within 1.12- and 1.25-mb intervals on chromosome 3. Genetics 174:2203-13
Nestor, Andrea L; Cicila, George T; Karol, Seth E et al. (2006) Linkage analysis of neointimal hyperplasia and vascular wall transformation after balloon angioplasty. Physiol Genomics 25:286-93