Spatiotemporal transregulation of D1-like angiotensin receptors in genetically...

D1 样血管紧张素受体在遗传上的时空反常调节

• 批准号: 8625321
• 负责人: Robin A Felder
• 金额: $ 42.15万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625321
• 关键词: Adrenal Glands; Adult; Angiotensin Receptor; Angiotensins; Antihypertensive Agents; Binding; Blood Pressure; CAV1 gene; Cardiovascular system; Caveolins; Cell Line; Cell membrane; Cell physiology; Cells; Chronic; Complex; Coupled; Critical Pathways; Cyclic AMP; Data; Development; Disease; Distal; Dopamine; Dopamine Receptor; Ensure; Environmental Risk Factor; Epithelium; Equilibrium; Essential Hypertension; Etiology; Excretory function; Failure; Fluorescence Resonance Energy Transfer; Fluorescent Dyes; Fractionation; Functional disorder; GRK4 gene; GTP-Binding Proteins; Genetic Transcription; Genetic Variation; Genotype; Goals; Hour; Human; Hypertension; Individual; Intake; Intracellular Second Messenger; Kidney; Lead; Limb structure; Link; Location; Low Income Population; Measurement; Measures; Mediating; Medicare/Medicaid; Membrane; Membrane Microdomains; Metabolism; Methods; Modeling; Molecular; Nephrons; Neuraxis; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Phosphotransferases; Physiology; Process; Production; Proximal Kidney Tubules; Receptor, Angiotensin, Type 1; Regulation; Regulatory Pathway; Research Proposals; Resolution; Role; Scaffolding Protein; Second Messenger Systems; Seminal; Signal Transduction; Sodium; Space Perception; Structure; Sucrose; System; Techniques; Testing; Therapeutic; Thick; Time; Translations; Tubular formation; Variant; Vascular resistance; Work; adapter protein; base; blood pressure regulation; caveolin 1; desensitization; familial hypertension; genetic variant; improved; insight; new therapeutic target; normotensive; pressure; receptor; receptor upregulation; response; salt sensitive hypertension; saluretic; second messenger; sensor; sodium green; spatiotemporal

G protein-coupled kinase type 4 (GRK4) gene variants (R65L, A142V, and A486V) selectively desensitizes the dopamine-1 receptor (DIR) and not the D5R, which upregulates the angiotensin type 1 receptor (ATIR). The net result of a desensitized DIR (natriuretic) and upregulated ATIR (antinatriuretic) is a net sodium reabsorption by the kidney. However, the molecular mechanisms responsible for DIR desensitization, ATIR upregulation, and the integration of these two pathways on net sodium metabolism are not well understood. We hypothesize that the membrane localization and ultimate activity of the DIR, D5R, and ATIR are regulated by oligomerization and spatial orientation via scaffolding proteins (e.g. caveolin-l (CAV1)), which ultimately regulate their interaction with intracellular second messengers. Specifically, GRK4 binds to caveolin-l (CAV1) which is interrupted by the presence of gene variants. We further hypothesize that a molecular trimeric D1R/CAV1/GRK4 association may be necessary for dopaminergic inhibition of NaKATPase activity via intracellular internalization in conjunction with adapter protein-2 (AP-2). Specific Aim 1 will examine the spatiotemporal transregulation of the DIR, D5R, ATIR, and CAV1 and their link to intracellular second messengers. In order to increase the relevance of our studies to human physiology and pathophysiology, we will study these phenomenon in 60 human renal proximal tubular cells (RPTCs) lines that have been genotyped for GRK4 variants. Specific Aim 2 will study spatiotemporal transregulation of the DIR, D5R, ATIR, and CAVIand their effect on the activity of the principal sodium transporters in human RPTCs NaKATPase and NHE3. The study of the effect of gene variants of GKR4 on the single RPTC physiology representing wide genetic diversity will improve our understanding of how the renal proximal tubule controls renal sodium excretion, and lead to potential novel therapeutic targets for the development of targeted and personalized antihypertensive therapeutics.

G蛋白偶联激酶4（GRK 4）基因变异体（R65 L、A142 V和A486 V）选择性脱敏 多巴胺-1受体（D5 R）而不是D5 R，D5 R上调血管紧张素1型受体（ATIR）。 脱敏的利钠尿和上调的ATIR的净结果是钠的净释放。 肾脏的重吸收。然而，分子机制，负责的药物脱敏，ATIR 上调，以及这两种途径对净钠代谢的整合还没有很好地理解。 我们假设，膜定位和最终活性的ESTA，D5 R，和ATIR是 通过支架蛋白（例如小窝蛋白-1（CAV 1））的寡聚化和空间取向来调节， 最终调节它们与细胞内第二信使的相互作用。具体地，GRK 4结合至 Caveolin-1（CAV 1），其被基因变体的存在中断。我们进一步假设， 分子三聚体D1 R/CAV 1/GRK 4联合可能是多巴胺能抑制所必需的 NaKATP酶活性通过与衔接蛋白-2（AP-2）结合的细胞内内化。具体目标 1将研究p53、D5 R、ATIR和CAV 1的时空反式调节及其与 细胞内第二信使为了增加我们的研究与人类生理学的相关性， 病理生理学，我们将研究这些现象在60人肾近端小管细胞（RPTC）系 已经进行了GRK 4变异基因分型。具体目标2将研究时空的反调节， D5 R、ATIR和CAVI及其对人体主要钠转运蛋白活性的影响 RPTC NaKATP酶和NHE 3。GKR 4基因变异对单个RPTC影响的研究 代表广泛遗传多样性的生理学将提高我们对肾脏近端如何发挥作用的理解 肾小管控制肾钠排泄，并导致潜在的新的治疗靶点的发展， 靶向和个性化的抗高血压治疗。