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PKD proteins in endothelial cells

内皮细胞中的 PKD 蛋白

基本信息

批准号：
10097912
负责人：
Jonathan H Jaggar
金额：
$ 60.23万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10097912
关键词：
Acetylcholine Arteries Attenuated Biotinylation Blood Pressure Blood Vessels Blood flow Calcium Cardiovascular Diseases Cell Line Cell Wall Cell physiology Coupling Data Electrophysiology (science)Endothelial Cells Endothelium Fluorescence Resonance Energy Transfer Genetic Models Hypertension Image Immunofluorescence Immunologic Impairment Knock-out Knockout Mice Ligands Light Lighting Mediating Membrane Potentials Methods Microscope Modification Mus Myography Nitric Oxide Synthase Organ PKD2 protein Pathologic Pathway interactions Pharmacology Physiological Potassium Channel Process Proteins RNA Interference Receptor, Angiotensin, Type 1 Regulation Resistance Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Stimulus Superoxide Dismutase Systemic blood pressure TRP channel Telemetry Tertiary Protein Structure Testing Transmembrane Domain Vasodilation Vasodilator Agents Western Blotting Wnt proteins autocrine cell type mimetics novel patch clamp polycystic kidney disease 1 protein protein kinase D protein phosphatase inhibitor-2 response

项目摘要

Project Summary Endothelial cells line the wall of all blood vessels and regulate a wide variety of functions, including contractility which controls systemic blood pressure. Dysfunctional endothelial cells are a hallmark of several cardiovascular diseases, but pathological mechanisms involved are poorly understood. Endothelial cells express both PKD1 (polycystin-1), an eleven transmembrane domain protein, and PKD2 (polycystin-2), a transient receptor potential (TRP) channel. Regulatory mechanisms, physiological functions and pathological involvement during hypertension of PKD1 protein and PKD2 channels in endothelial cells are unclear. Using a wide variety of approaches and inducible, endothelial cell-specific knockout mice, we provide evidence that physical coupling of PKD1 to PKD2 in endothelial cells stimulates vasodilation. Preliminary data also suggest that PKD1/PKD2 channel signaling is dysfunctional during hypertension, which attenuates this vasodilatory signaling mechanism. In this proposal, we will investigate three specific aims. Aim 1 will test the hypothesis that endothelial-dependent physiological stimuli activate PKD1/PKD2 coupling in endothelial cells, leading to vasodilation. Aim 2 will investigate the mechanisms by which endothelial-dependent stimuli activate PKD1/PKD2 channels in endothelial cells to produce vasodilation. Aim 3 will study the hypothesis that hypertension is associated with pathological alterations in PKD1/PKD2 channel signaling in endothelial cells that inhibits vasodilation mediated by these proteins. Methods used will include RT-PCR, Western blotting, biotinylation, FRET, RNAi, co-IP, immunofluorescence, patch-clamp electrophysiology, membrane potential recording, intracellular Ca2+ imaging, arterial myography and blood pressure telemetry. This project will provide significant novel information concerning vasoregulation by endothelial cell PKD1 and PKD2 proteins.

项目总结