BLOOD PRESSURE CANDIDATE GENE SCREENING--A NEW PARADIGM

描述：(改编自《调查者摘要》) 导致高血压的机制(及其背后的基因)需要 以更好地了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中的压力。申请者已链接 大鼠3号和7号染色体上的血压数量性状基因座 用盐敏感自交系(S)和自交系选育的分离群体 耐盐(R)大鼠喂食高盐饮食。R-鼠源性基因的导入 含有这两个QTL的染色体区域导入S大鼠导致同源基因 与S相比，血压和心脏质量显著降低的菌株 大鼠，证实BP QTL在BPQTL的导入区存在 3号和7号染色体。其他人也使用了类似的方法来开发 携带BP QTL的同源菌株位于其他六条染色体上，导致 在一组来自Dahl大鼠血液模型的8个同源菌株中 压力盐敏性。申请人假设一个潜在的基因(S) 在已知BP的情况下，QTL可能在靶器官/组织中差异表达。如果是的话， 这样的基因在同源菌株中也应该有不同的调控。 携带不同的碱基QTL。控制QTL效应的基因(S)应表现出 靶标中的同源菌株特异性差异表达模式 器官(S)，并应映射到该特定个体携带的染色体间隔 同源菌株。因此，具有这种特征的基因将是更优越的 候选基因至少部分负责特定的BP QTL。这个 申请人建议确定BP QTL的候选基因如下： 将在S和R的肾脏中发现差异表达的基因 低盐(遗传差异)和高盐饮食的大鼠 (对盐敏感)。这些差异表达基因的肾脏RNA表达 将在一组携带Dahl鼠BP QTL的同源菌株中进行检查，其中 每个菌株都携带一个低血压等位基因，对应于一个不同的 S-大鼠等位基因背景。具有同源菌株特异性模式的基因 将绘制差异基因表达图谱，以确定它们的基因组 地点。具有1)同源菌株特异性差异基因模式的基因 表达和2)定位到包含一个 特定的BP QTL，将被认为是该基因的有力候选者(S) 负责与该QTL相关的血压差异。这是一项新的 该方法应加快确定强候选基因的速度 特定的BP QTL，以及潜在的新的血压调节 机械装置。

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.