Study of ANP Receptor:Gene Targeting and Expression

项目摘要 已知调节血压的机制具有很强的遗传成分;然而， 参与高血压发病机制的特定基因尚未明确。关键调节器是心房和 脑利钠肽（ANP，BNP）通过其同源的利钠肽受体-A（NPRA）信号传导 和第二信使cGMP。ANP-BNP/NPRA系统在血液调节中起重要作用 血压和肾血管稳态。基因的多态性有很强的关联， 编码ANP（Nppa）、BNP（Nppb）和NPRA（Npr 1）与高血压和心血管功能障碍有关 在人类身上。这些表型可以使用全局Npr 1基因敲除系统在小鼠中重现。两 缺乏全局Npr 1基因（Npr 1-/-）的雄性和雌性小鼠表现出高血压，但特别是雄性Npr 1 小鼠在成年时患有高血压、心力衰竭和猝死。目前尚不清楚缺乏 肾脏和脉管系统特定细胞类型中的NPR 1逐渐导致高血压， 是在全局Npr 1-/-小鼠中观察到的性别差异的基础。Npr 1缺失表现出恶性 小鼠高血压是显著的，补充了Nppa、Nppb和 NPR 1在人类对Npr 1缺乏如何不同地影响血液的机制的理解 与性有关的压力仍然是一个重要但尚未得到解答的问题。我们假设细胞- Npr 1的特异性缺失在肿瘤的分子和细胞扰动的发展中起着关键作用。 导致Toll样受体（TLR）活化的免疫原性和炎症机制，氧化还原敏感性 转录因子核因子κ B（NF-κB）、适应性T细胞和巨噬细胞。的长期目标 该建议旨在确定导致免疫原性慢性炎症的分子和遗传因素， 炎症导致高血压和肾血管功能障碍。建议的总体目标 研究的目的是确定肾单位小管（NT）和血管平滑肌的损失的机制方面， 肌细胞（SMC）特异性Npr 1，导致高血压和肾血管重塑和功能障碍。的 核心假设是肾脏和血管系统中Npr 1的细胞特异性丢失触发了 免疫原性和炎症过程，引起高血压和终末器官损伤， 依赖的方式。所提出的具体目标将检验以下假设：1）损伤相关免疫 受体有助于高血压和肾血管功能障碍; 2）下游氧化还原敏感性 级联触发高血压和肾血管损伤和功能障碍;和3）免疫原性 机制引起高血压和肾血管疾病。成功完成拟议的 研究可能会导致识别急需的新生物标志物和治疗方法， 预防人类两种性别的高血压和肾血管功能障碍。

PROJECT SUMMARY The mechanisms regulating blood pressure are known to have strong genetic components; however, the specific genes involved in the pathogenesis of hypertension are not well defined. Key regulators are atrial and brain natriuretic peptides (ANP, BNP) signaling through their cognate natriuretic peptide receptor-A (NPRA) and the second messenger cGMP. The ANP-BNP/NPRA system plays critical roles in the regulation of blood pressure and reno-vascular homeostasis. There is a strong association of polymorphisms in the genes that encode ANP (Nppa), BNP (Nppb), and NPRA (Npr1) with high blood pressure and cardiovascular dysfunction in humans. These phenotypes can be recapitulated using global Npr1 gene-knockout system in mice. Both male and female mice lacking global Npr1 gene (Npr1-/-) exhibit high blood pressure, but specifically male Npr1 mice suffer from hypertension, heart failure, and sudden death at adult age. It is not clear how the lack of Npr1 in the specific cell-types of kidneys and vasculature progressively leads to hypertension, nor what underlies the observed sex-differences in the global Npr1-/- mice. The Npr1 deletion exhibiting malignant hypertension in mice is significant and complements clinical findings of polymorphisms in Nppa, Nppb, and Npr1 in humans. The mechanistic understanding of how the absence of Npr1 divergently affects blood pressure in a sex-related manner remains an important yet unanswered question. We hypothesize that cell- specific deletion of Npr1 plays critical roles in the development of molecular and cellular perturbations of immunogenic and inflammatory mechanisms leading to activation of Toll-like receptors (TLRs), redox-sensitive transcription factor nuclear factor kappa B (NF-κB), adaptive T cells, and macrophages. The long-term goal of this proposal is to determine the molecular and genetic factors that contribute to immunogenic chronic inflammation leading to hypertension and reno-vascular dysfunction. The overall objective of the proposed studies is to determine the mechanistic aspects of the loss of nephron tubules (NT)- and vascular smooth muscle cell (SMC)-specific Npr1, leading to hypertension and reno-vascular remodeling and dysfunction. The central hypothesis is that the cell-specific loss of Npr1 in the kidneys and vasculature triggers the immunogenic and inflammatory processes that provoke hypertension and end-organ damage in a sex- dependent manner. The proposed specific aims will test the hypotheses: 1) the damage-associated immune receptors contribute to hypertension and reno-vascular dysfunction; 2) the down-stream redox-sensitive cascades trigger high blood pressure and renal-vascular injury and dysfunction; and 3) immunogenic mechanisms provoke hypertension, and renal-vascular disorders. The successful completion of the proposed studies could lead to the identification of much-needed new biomarkers and therapies for the treatment and prevention of hypertension and renal-vascular dysfunction in both genders in humans.