The applicant's long-term goal is to be an independent investigator using gene targeting to study the genetics of cardiovascular diseases. An important candidate gene for hypertension and atherosclerosis in humans is the angiotensin-converting enzyme (ACE) gene (ACE) which codes for a somatic form of ACE found throughout the body and a testis-specific form of ACE found only in developing spermatogenic cells. During his initial research training, the applicant generated mice having a mutation in the ACE gene that inactivates both forms of ACE. Surprisingly, male but not female heterozygous mice have a decrease in blood pressure compared to normal mice, although both male and female heterozygous mice have decreased serum ACE activities. Additionally, homozygosity for the mutation greatly affects the fertility of male but not female mice. The proposed research centers on plans to further explore the ACE gene and its role in blood pressure regulation and reproduction.
Four specific aims were chosen: (i) To determine the blood pressure effects of a genetically determined increase in expression of both forms of ACE. (ii) To determine the blood pressure effects of mutations that alter expression of the somatic and testis forms of ACE independently. (iii) To investigate the underlying mechanisms for the fertility defect in mice homozygous for disruption of the ACE gene, and compare the breeding outcomes of mice having the mutations in the ACE gene planned under specific Aims (i) and (ii). (iv) To study the interactions of mutations in the ACE gene with mutations in other genes that influence the cardiovascular system, such as the disruption of the apolipoprotein E gene that causes atherosclerosis in mice. The proposed environment for these studies is ideal. The Smithies laboratory has a major focus on generating and characterizing mutant mice for studying the genetics of hypertension and atherosclerosis. Techniques for reliably evaluating the blood pressures of mice have been developed. Techniques for embryo manipulation and evaluation of atherosclerosis in mice, as well as mice having mutations in other cardiovascular genes are present in the laboratory and will be valuable in the achievement of aims (ii) and (iii). Achievement of the proposed aims will lead to improved understanding of the role of the ACE gene in cardiovascular diseases and fertility and may open avenues into the study of contraception.
| Hodgin, J B; Krege, J H; Reddick, R L et al. (2001) Estrogen receptor alpha is a major mediator of 17beta-estradiol's atheroprotective effects on lesion size in Apoe-/- mice. J Clin Invest 107:333-40 |
| Hagaman, J R; Moyer, J S; Bachman, E S et al. (1998) Angiotensin-converting enzyme and male fertility. Proc Natl Acad Sci U S A 95:2552-7 |
| Krege, J H; Kim, H S; Moyer, J S et al. (1997) Angiotensin-converting enzyme gene mutations, blood pressures, and cardiovascular homeostasis. Hypertension 29:150-7 |
| Shesely, E G; Maeda, N; Kim, H S et al. (1996) Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 93:13176-81 |
