The aims of this proposal are to develop gene constructs of the kallikrein-kinin system, the renin-angiotensin system and atrial natriuretic peptide (ANP) and to evaluate their therapeutic potential in hypertensive animal models. These genes are amenable to in vitro manipulations because the genes have been cloned and the genetic and regulatory parameters extensively studied. The proposed approaches are based on the applicant's preliminary studies which showed that human tissue kallikrein and ANP gene constructs delivered by intravenous and intramuscular injections are expressed in vivo and that somatic gene delivery caused sustained blood pressure reduction in SHR. The applicant plans to further explore this technology including renin and angiotensin converting enzyme (ACE) antisense constructs in the study. The potential advantage of liposome and recombinant adenovirus-mediated gene delivery will also be explored.
The specific aims are (1) to produce tissue kallikrein, kinin and ANP gene constructs for general and targeted delivery, (2) to deliver the kallikrein, kinin and ANP gene constructs and to determine their relative efficiency in reducing blood pressure in hypertensive rats, (3) to evaluate the potential blood pressure lowering effect of renin and ACE antisense constructs delivered alone or in combination with kallikrein and ANP gene delivery, and (4) to explore the effectiveness of transplacental and postnatal gene delivery to SHR fetuses and newborns and to evaluate the potential effect in preventing the development of high blood pressure in these animals. These studies will determine the suitability of several vectors and delivery techniques for the in vivo delivery of genes of potential therapeutic value. In addition, they will provide new tools to manipulate the introduction of genes at various levels for studying cardiovascular and renal function in experimental animals. The long term goal is to explore the possibility of applying this new technology to the cardiovascular system as it pertains to blood pressure regulation and the management of hypertension.
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