Study of ANP Receptor:Gene Targeting and Expression

ANP受体的研究：基因打靶与表达

• 批准号: 9310905
• 负责人: Kailash N Pandey
• 金额: $ 37.63万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310905
• 关键词: Adult; Affect; Age; Age-Months; Animals; Atrial Natriuretic Factor Receptors; Biological Markers; Blood Pressure; Blood Vessels; Brain natriuretic peptide; Cardiovascular system; Cells; Cessation of life; Chronic; Clinical; Complement; Congestive Heart Failure; Cyclic GMP; Data; Development; Disease; Elements; Exhibits; Female; Functional disorder; Gender; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Goals; Guanylate Cyclase; Heart Atrium; Heart failure; Homeostasis; Human; Hypertension; Immune; Immunologic Receptors; Immunologics; Impairment; Inflammation; Inflammatory; Injury; Investigation; Kidney; Kidney Diseases; Lead; Malignant Hypertension; Molecular; Molecular Genetics; Mus; Muscle Cells; NF-kappa B; Nephrons; Organ; Oxidation-Reduction; Pathogenesis; Pathway interactions; Phenotype; Play; Process; Proteins; Publishing; Renal Vascular Disorder; Renal tubule structure; Risk Factors; Role; Second Messenger Systems; Sex Characteristics; Signal Transduction; Smooth Muscle Myocytes; Stroke; Sudden Death; System; T-Lymphocyte; Testing; Therapeutic; Toll-like receptors; Tubular formation; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Woman; Work; atrial natriuretic factor receptor A; base; blood pressure regulation; cell type; chemokine; cytokine; disorder prevention; expectation; hypertension prevention; immunogenic; insight; kidney vascular structure; knockout gene; macrophage; male; men; molecular targeted therapies; mortality; mouse model; novel; receptor; response; sex; transcription factor

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.

项目概要 众所周知，调节血压的机制具有很强的遗传成分。 参与高血压发病机制的具体基因尚未明确，关键调节因子是心房和。 脑钠尿肽（ANP、BNP）通过其同源钠尿肽受体-A (NPRA) 发出信号 第二信使cGMP在血液调节中发挥着重要作用。 压力和肾血管稳态之间存在密切的基因多态性关联。 编码 ANP (Nppa)、BNP (Nppb) 和 NPRA (Npr1) 与高血压和心血管功能障碍 这些表型可以在小鼠中使用全局 Npr1 基因敲除系统来重现。 缺乏整体 Npr1 基因 (Npr1-/-) 的雄性和雌性小鼠表现出高血压，但特别是雄性 Npr1 小鼠在成年后会出现高血压、心力衰竭和猝死，目前尚不清楚这是如何缺乏的。 肾脏和脉管系统特定细胞类型中的 Npr1 逐渐导致高血压，也不是什么 Npr1-/- 小鼠中观察到的性别差异是 Npr1 缺失表现出恶性的基础。 小鼠高血压具有重要意义，并且补充了 Nppa、Nppb 和 Nppa 多态性的临床发现 人类中 Npr1 的缺失如何不同地影响血液的机制理解。 与性相关的压力仍然是一个重要但尚未解答的问题。 Npr1 的特异性缺失在分子和细胞扰动的发展中起着关键作用 导致氧化还原敏感的 Toll 样受体 (TLR) 激活的免疫原性和炎症机制 转录因子核因子κB (NF-κB)、适应性T细胞和巨噬细胞的长期目标。 该提案旨在确定导致免疫原性慢性病的分子和遗传因素 炎症导致高血压和肾血管功能障碍。所提出的总体目标。 研究的目的是确定肾单位小管（NT）和血管平滑度损失的机制 肌细胞 (SMC) 特异性 Npr1，导致高血压和肾血管重塑和功能障碍。 中心假设是肾脏和脉管系统中 Npr1 的细胞特异性丢失会触发 免疫原性和炎症过程会引起高血压和终末器官损伤 所提出的具体目标将检验以下假设：1）损伤相关免疫。 受体导致高血压和肾血管功能障碍；2) 下游氧化还原敏感 级联反应引发高血压和肾血管损伤和功能障碍；3) 免疫原性 引发高血压和肾血管疾病的机制已成功完成。 研究可能会导致鉴定急需的新生物标志物和治疗方法 预防人类两性的高血压和肾血管功能障碍。