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Role of Non-visual Opsins in Light-dependent Apoptosis of Pulmonary Arterial Smooth Muscle Cells in Pulmonary Arterial Hypertension

非视觉视蛋白在肺动脉高压肺动脉平滑肌细胞光依赖性凋亡中的作用

基本信息

批准号：
10025576
负责人：
Gautam Sikka
金额：
$ 6.13万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10025576
关键词：
Affect Age Apoptosis Apoptotic Award Biological Assay Biology Blood Vessels Blood capillaries CASP3 gene Caspase Cell Death Cells Characteristics Cleaved cell Control Animal Coupled Cyclic Nucleotides DNA Nucleotidylexotransferase Disease Disease Progression Drug Targeting Enzymes Exposure to Funding G protein coupled receptor kinase G-Protein-Coupled Receptors Gender Genetic Goals Hypoxia Immunoblot Analysis In Vitro Label Lesion Light Literature Lung Measures Mediating Messenger RNA Methods Modeling Molecular Morbidity - disease rate Morphology Nuclear Opsin Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphotransferases Photoreceptors Phototherapy Potassium Channel Predisposition Process Proteins Pulmonary artery structure Pulmonary vessels Race Rattus Regulation Relaxation Research Research Personnel Resistance Rodent Role Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Specificity Stains Stimulus Testing Time Training Vascular Diseases Vascular remodeling Vasodilation Viral Work beta-arrestin differential expression effective therapy experimental study in vivo insight lung hypoxia mortality nexin novel overexpression pressure prevent programs protein expression pulmonary arterial hypertension receptor response side effect skills therapeutic target voltage

项目摘要

PROJECT SUMMARY/ ABSTRACT: Pulmonary arterial hypertension (PAH), a progressive and deadly condition characterized by pre-capillary disease with vaso-occlusive lesions and severe elevations in pulmonary arterial pressure, is attributed to both loss of vascular relaxation and severe vascular remodeling. Significant dysregulation of apoptosis, or programmed cell death, in pulmonary arterial smooth muscle cells (PASMCs) prevents turnover of abnormal PASMCs and contributes significantly to vascular remodeling. Currently approved treatments target vasodilation and slow progression of PAH, but drugs targeting reversal of vascular remodeling, and particularly cell death, that can serve as effective therapies to reverse disease have yet to be identified. We recently discovered the presence photoreceptors, or opsins, in rodent systemic and pulmonary blood vessels and elucidated the pathway by which they mediate vasorelaxation in response to blue light. In pulmonary arterial smooth muscle cells (PASMCs), we recently found that blue light exposure also selectively induces cell death in PASMCs from a model of PAH. In contrast, in normal PASMCs, apoptosis can be induced by blue light only when G protein-coupled receptor kinase-2 (GRK2), a negative regulator of opsin activity, is inhibited. Thus, the focus of my proposal is to explore this intriguing finding and elucidate the mechanism by which blue light induces apoptosis. We will employ the Sugen-hypoxia rat model of severe PAH to isolate PASMCs used in in vitro experiments. In Specific Aim 1, we will determine whether expression of opsin receptors is increased or expression of GRK2 is decreased, in PAH PASMCs. In Specific Aim 2, we will measure intracellular K+ ([K+]i) to determine if blue light exposure increases the susceptibility to apoptosis, in of PAH PASMC through efflux of K+ via cyclic nucleotide-gated K+ channels, and in Specific Aim 3, we will measure cleaved (active) caspase-3 levels and activity to determine whether blue light exposure increases caspase-3 activity in PAH PASMCs. With the completion of the research proposed in this application, we will characterize a completely novel, wavelength-specific, light-activated molecular switch, which could be harnessed for treatment of PAH to prevent and potentially reverse remodeling by selectively restoring apoptosis in abnormal PASMCs. The funds from this award will not only allow for the training necessary for the applicant to realize this goal, but also provide the opportunity to begin developing methods for in vivo application of the results.

项目摘要/摘要：