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BLOOD PRESSURE CANDIDATE GENE SCREENING--A NEW PARADIGM

血压候选基因筛选——新范式

基本信息

批准号：
6390290
负责人：
GEORGE T CICILA
金额：
$ 21.65万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2003-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6390290
关键词：
angiotensin /renin /aldosterone hypertension blood pressure dietary sodium disease /disorder model familial hypertension gene environment interaction genetic mapping genetic screening genetic strain genetic susceptibility laboratory rat nutrition related tag quantitative trait loci

项目摘要

DESCRIPTION: (Adapted from the Investigator's Abstract) The essential mechanisms (and the genes underlying them) leading to hypertension need identification for better understanding and treatment of this complex disorder. The most direct way of accomplishing this is to identify genes regulating blood pressure in animal models of genetic hypertension. The applicants have linked loci on rat chromosomes 3 and 7 to blood pressure quantitative trait loci (BP QTL) in a segregating population bred from inbred Dahl salt-sensitive (S) and salt-resistant (R) rats fed a high salt diet. Introgression of R-rat derived chromosomal regions containing these two QTLs into S rats resulted in congenic strains with significantly lower blood pressure and cardiac mass compared to S rats, confirming the presence of BP QTL in the introgressed regions of chromosomes 3 and 7. Similar methodology has been used by others to develop congenic strains carrying BP QTLs located on six other chromosomes, resulting in a panel of eight congenic strains derived from the Dahl rat model of blood pressure salt-sensitivity. The applicant hypothesizes that gene(s) underlying a given BP QTL may be differentially expressed in target organs/tissues. If so, such a gene should also be differentially regulated in congenic strains carrying different BP QTL. Gene(s) responsible for a QTL's effect should show a congenic strain-specific differential-pattern of expression in a target organ(s) and should map to the chromosomal interval carried by that particular congenic strain. Therefore, genes having such characteristics will be superior candidates as genes responsible for, at least in part, a specific BP QTL. The applicant proposes to identify candidate genes for BP QTL as follows: Differentially expressed genes will be identified in the kidneys of S and R rats, on both low NaCl (genetic-differences) and high NaCl diets (salt-responsive). Renal RNA expression of such differentially-expressed genes will be examined in a panel of congenic strains carrying Dahl rat BP QTL, where each strain carries a low blood pressure allele for a different BP QTL on a background of S-rat alleles. Genes having a congenic strain-specific pattern of differential gene expression will be mapped to determine their genomic location. Genes with a 1) congenic strain-specific pattern of differential gene expression and 2) mapping to the introgressed chromosomal region containing a specific BP QTL, will be considered strong candidates for the gene(s) responsible for blood pressure differences associated with this QTL. This new approach should accelerate the identification of strong candidate genes for particular BP QTL and, potentially, of new blood pressure regulatory mechanisms.

描述：（改编自研究者摘要）导致高血压的机制（及其基因）需要鉴定，以便更好地理解和治疗这种复杂的疾病。实现这一目标的最直接方法是识别调节血液的基因遗传性高血压动物模型的血压。申请人已联系大鼠3号和7号染色体上的基因座与血压数量性状基因座（BP QTL）在由自交系Dahl盐敏感（S）和耐盐（R）大鼠喂食高盐饮食。R-大鼠源性基因渗入将含有这两个QTL的染色体区域导入S大鼠，与S相比，血压和心脏质量显著降低的菌株大鼠，证实BP QTL的存在下，在渗入区域的 3号和7号染色体。其他人也使用类似的方法来开发在其它6条染色体上携带BP QTL的同源株系，在一组来自Dahl大鼠血液模型的8个同源株中，压力盐敏性申请人假设，在一个或多个基因的基础上，给定的BP QTL可能在靶器官/组织中差异表达。如果是这样的话，这样的基因在同类菌株中也应该受到不同的调节携带不同的BP QTL。负责QTL效应的基因应该表现出同源株特异性差异-在靶中的表达模式器官，并应映射到该特定器官携带的染色体间隔同类品系因此，具有这些特征的基因将是优越的上级候选基因负责，至少部分，一个特定的BP QTL。的申请人建议如下鉴定BP QTL的候选基因：将在S和R的肾脏中鉴定差异表达的基因大鼠，低NaCl（遗传差异）和高NaCl饮食（盐敏感）。这种差异表达基因的肾RNA表达将在一组携带Dahl大鼠BP QTL的同源品系中进行检查，其中每个菌株携带一个低血压等位基因，用于不同的BP QTL上， S-rat等位基因的背景具有同源菌株特异性模式的基因将绘制差异基因表达图，以确定它们的基因组位置.具有1）同源株特异性差异基因模式的基因表达和2）定位到含有一个基因的渗入的染色体区域，特定的BP QTL，将被认为是基因的强候选者与此QTL相关的血压差异。这个新这种方法应该加速识别强有力的候选基因，特定的BP QTL，以及潜在的新的血压调节基因，机制等