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Non-Visual Opsins & Vasoregulation: Implications for Vascular Therapy

非视觉视蛋白

基本信息

批准号：
9264005
负责人：
DAN E BERKOWITZ
金额：
$ 40.29万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264005
关键词：
ADRBK1 gene Adenoviruses Adrenergic Agents Arrestins Arteries Blood Blood Circulation Blood Vessels Blood flow Cells Cephalic Circadian Rhythms Complement Coronary Arteriosclerosis Cutaneous Cyclic GMP-Dependent Protein Kinases Data Disease Dominant-Negative Mutation Dose Electrodes Electrophysiology (science)Endothelium Erectile dysfunction Exhibits Fingers Functional disorder G protein coupled receptor kinase G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Grant Health Human Hypertension Immunohistochemistry Impairment Injury Invertebrate Photoreceptors Invertebrates Lasers Light Measurement Mediating Membrane Potentials Microdialysis Molecular Mus Muscle Cells Myography Nitric Oxide Synthase Opsin Pain Paroxetine Pathway interactions Patients Pharmacology Phosphotransferases Physiological Potassium Channel Process Protein Isoforms Proteins Publications Rattus Raynaud Disease Recording of previous events Regulation Relaxation Retinal Ganglion Cells Reverse Transcriptase Polymerase Chain Reaction Role Scleroderma Signal Pathway Signal Transduction Signal Transduction Pathway Skin Sleep Smooth Muscle Myocytes Soluble Guanylate Cyclase Stimulus Stroke Tail Techniques Testing Tissues Universities Vascular Diseases Vascular Smooth Muscle Vasodilation Vasomotor Vertebrates Visual base beta-adrenergic receptor constriction desensitization experimental study in vivo inhibitor/antagonist insight knock-down light intensity melanopsin mouse model mutant new therapeutic target novel overexpression phosphodiesterase 6 prevent public health relevance receptor response small hairpin RNA small molecule inhibitor targeted treatment vascular bed vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Impaired vasomotor function mediated by pertubations in neurohumoral signaling and/or impaired endothelial function is the proximate cause of vascular diseases such as hypertension, coronary artery disease, stroke, erectile dysfunction, and specific vasculopathies such as Raynaud's phenomenon (RP). The identification of novel pathways that regulate vascular tone provides new targets for treatment of vascular disorders. We have recently identified a novel mechanism that modulates vascular tone. Melanospin (Opn4) are classically found in the retinal ganglion cells where they regulate circadian rhythm and sleep. We have identified a non-visual light (opsin) receptor, Opn4, in blood vessels from a number of mammalian species, and from number of vascular beds. These receptors mediated intensity-dependent vasorelaxation to light of a specific wavelength (blue 430-460nM). Preliminary data suggest that signal transduction mechanism(s) involve soluble guanylate cyclase and phosphodiesterase 6 but not protein kinase G. Light activation leads to vascular hyperpolarization a process that involves K+ channels. The receptor is likely regulated as a classic G-protein coupled receptor in that inhibition of G-protein receptor kinase prevents stimulus-dependent desensitization and significantly decrease the light intensity needed to produce a relaxation response. Finally, in vivo, blue light is able evoke a physiologic response; significantly increasing blood flow in the mouse tail artery. We hypothesize that 1) Opn4 is an important regulator of vasodilatory function and mediates a physiologic function in vivo; 2) the signal transduction mechanism in vessels mimics visual opsins of vertebrates or "simple" photoreceptors of invertebrates; 3) desensitization/regulation occurs by a GRK2/arrestin mechanism; and 4) this pathway is upregulated in diseases in which NO signaling (vasodilation) is impaired and vasocontriction is enhanced such as RP. In this proposal, we plan to: 1) Further characterize the potential physiologic role of Opn 4 in vasoregulation utilizing Opn4-/- mice and newly discovered Opn4 inhibitors, opsinamides, using myography in isolated vessels and laser doppler in cranial windows as endpoints in vivo; 2) Determine signal transduction mechanism/s from receptor and G protein to channel with sharp electrode measurement of membrane potential in isolated vessels using specific inhibitors and shRNA knockdown of pathway proteins; 3) Understand receptor regulation using novel pharmacologic inhibitor of GRK2, paroxetine, vascular smooth muscle-selective GRK2-/-, and arrestin-/- mice, as well as GRK2 and arrestin shRNA adenovirus knockdown in isolated vessels. 4) Determine the role of Opn4 receptors as a target in mouse models of RP and explore mechanisms mediating photorelaxation in vivo in the cutaneous circulation of healthy humans and those with primary RP using laser flow doppler and skin microdialysis. In this way we hope to gain insight into the function and dysfunction of this novel pathway in health and disease, and determine its potential as a novel therapeutic target.