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Integrating novel mechanisms controlling sodium excretion and blood pressure

整合控制钠排泄和血压的新机制

基本信息

批准号：
9922350
负责人：
DAVID M POLLOCK
金额：
$ 225.97万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922350
关键词：
ARNTL gene Accounting Acetylation Adult American Angiotensins Animal Model Animals Attention Awareness Biology Blood Circulation Blood Pressure Blood Vessels Body Fluids Breeding Businesses Cardiovascular Diseases Cardiovascular system Cell physiology Cilia Clinical Collecting Cell Complement Deacetylation Defect Disease Duct (organ) structure Ductal Epithelial Cell Electrolyte Balance Electrolytes Elements Endothelin Endothelin Receptor Antagonist Endothelin-1 Ensure Enzymes Equilibrium Estrogens Excretory function Future Genes Genotype Goals Gonadal Steroid Hormones HDAC1 gene Health Histone Deacetylase Homeostasis Human Hypertension Immune System Diseases In Vitro Inflammatory Kidney Kidney Diseases Knowledge Laboratories Lead Liquid substance Mediating Mediator of activation protein Molecular Monitor NOS1 gene NOS3 gene Nitric Oxide Pathway interactions Patients Peptides Pharmaceutical Preparations Physiological Population Process Production Program Development Program Research Project Grants Receptor Activation Regulation Regulatory Pathway Renin Research Personnel Risk Risk Factors Rodent Role Schedule Scheme Sex Differences Signal Transduction Sodium Sodium Chloride Statistical Data Interpretation System Techniques Testing Testosterone Therapeutic Time Tubular formation Variant Vasoconstrictor Agents Water blood pressure regulation cardiovascular risk factor circadian circadian pacemaker circadian regulation clinical development combat data management dietary salt fluid flow gene function hemodynamics high salt diet innovation meetings novel programs receptor salt intake saluretic side effect success synergism

项目摘要

OVERALL – PROJECT SUMMARY The long-term goal of this Program Project Grant (PPG) is to generate new information about how fluid- electrolyte balance is regulated and thus contributes to blood pressure control. Our studies largely focus on mechanisms related to endothelin-1 (ET-1) and its associated receptors, ETA and ETB. Previous studies from investigators on the project team revealed a significant role for this system in controlling renal handling of salt and water balance, control of renal hemodynamics, and blood pressure regulation. Investigators have demonstrated that defects in this system results in hypertension that is highly sensitive to dietary salt intake. This is a complicated yet powerful system that balances the vasodilatory and pro-natriuretic actions of the ETB receptor with the vasoconstrictor pro-inflammatory effects of ETA receptor activation. Exploring both renal tubular actions, primarily in the collecting duct, along with hemodynamic effects represents a diverse approach that is unique to this PPG. Our proposed program has several major themes that seek to elucidate novel mechanisms of renal control of sodium handling. In Project 1, we have evidence that ET-1 contributes to circadian regulation of blood pressure, and so we will explore how ET-1 impacts sodium excretion at different times of day. Project 2 will closely examine how alterations in renal tubular fluid flow that are associated with varying body fluid volume status modulate production of ET-1 within the collecting duct system and how it is regulated by the primary cilia, polycystins and other mediators. Recent findings from Project 3 have demonstrated a unique regulatory system involving acetylation and deacetylation of NOS1 in the collecting duct that impacts sodium handling and salt-dependent changes in blood pressure. Furthermore, both NOS1 and NOS3 are expressed in principal cells of the collecting duct, and so we have proposed a novel hypothesis whereby these two enzymes are regulating different aspects of cellular function. In addition, Projects 2 and 3 investigate how NOS1 and NOS3 in the collecting duct modulate both ET-1 production and actions. Finally, two cores support this PPG: the administrative core and the animal and analytical core. The administrative core manages and coordinates overall PPG activities, provides financial accounting and budgetary support, schedules and arranges meetings of PPG investigators, and manages statistical analysis and data management activities. Core B, the animal and analytical core, is responsible for managing breeding and genotyping for rodents in all three projects. In conclusion, these studies are expected to uncover important regulatory pathways that will aid our understanding of fluid-electrolyte and blood pressure control in health and in disease.

总体-项目总结