ù Identify the genes responsible for genetic hypertension, its associated conditions and its major complications in rat models of human hypertension.
ù Understand the mechanisms by which these genes influence blood pressure, the associated phenotypes and risk of end-organ damage.
ù Apply the data towards better understanding of the genetic basis of human hypertension and its complications.
Hypertension is a multifactorial trait with a strong (30-50%) but polygenic genetic component. Understanding the genetic basis of hypertension and its associated conditions is of fundamental importance if novel and specific approaches to both prevention and treatment are to be realised. In a previous Concerted Action (EURHYPGEN) under BIOMED 1 members of the network mapped several quantitative trait loci (QTLs) that influenced either (i) blood pressure (ii) associated phenotypes or (iii) end-organ damage, in crosses of genetically hypertensive and normnotensive rats. The objective of EURHYPGEN II is to move from this knowledge of the chromosomal location of the QTLs to the identification and characterisation of the causative genes themselves. For most QTLs the current precision of localisation is at the 20-30 cM level. The first aim is to narrow down the segment containing the QTL to 1-2 cM (the current limit of resolution by linkage). This will be achieved through the construction and phenotypic analysis of congenic strains containing increasingly smaller segments of the chromosomal regions of interest. Subsequently, physical mapping strategies will be used to identify the responsible genes. In the absence of obvious candidate genes to analyse, this will be based on (i) the assembly of a set of Yeast Artifical Chromosomes (YACs) containing the whole of the relevant chromosomal segment (ii) hybridisation of the set of YACs to mRNAs prepared from a variety of rat tissues (iii) cloning and characterisation of the RNAs that selectively hybridise and the corresponding genes (iv) investigation of the candidacy of the genes. At the same time, at the phenotypic level, the congenic lines will be compared with the parental (recipient) strains to dissect the physiological (molecular, cellular, tissue and whole body) mechanisms through which the gene mediates its effect and thus build up a fully integrated picture of both the genetic mutation as well as the phenotypic consequences.
Hypertension, Cardiovascular Diseases, Genetics, Genetic Models, Stroke, Linkage Analysis, Congenic Strains, Positional Cloning, YAC clones, Transcript maps