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The Role of the Nicotinic Cholinergic Pathway in Retinopathy of Prematurity

烟碱胆碱能通路在早产儿视网膜病变中的作用

基本信息

批准号：
8733170
负责人：
JOHN P COOKE
金额：
$ 39.38万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8733170
关键词：
Acetylcholine Affect Angiogenic Factor Arterial Fatty Streak Biochemical Biological Birth Blindness Blood Vessels Child Choline O-Acetyltransferase Cholinergic Receptors Choroid Choroidal Neovascularization Development Disease Drug Formulations Elements Endothelial Cells Exudative age-related macular degeneration Eye Genetic Growth Factor Human Volunteers Hypoxia Immunohistochemistry Impairment In Situ Hybridization Infant Inflammatory Ischemia Knockout Mice Lead Learning Ligands Malignant neoplasm of lung Mecamylamine Mediating Medicine Methods Modeling Mus Nature Neurons Nicotinic Receptors Pathogenesis Pathologic Neovascularization Pathway interactions Patients Permeability Phase Phase II Clinical Trials Phenotype Plasma Pregnancy Premature Infant Receptor Activation Research Retina Retinal Retinal Detachment Retinal Diseases Retinal Neovascularization Retinopathy of Prematurity Reverse Transcriptase Polymerase Chain Reaction Risk Factors Role Safety Sclera Signal Transduction Signaling Molecule Stimulation of Cell Proliferation Time Traction Tube Tumor Angiogenesis United States Vascular Endothelial Growth Factors Vascularization Vision angiogenesis base cancer cell choline transporter cholinergic diabetic human subject insight laser capture microdissection macular edema methyllycaconitine migration neovascularization neuron development novel novel strategies novel therapeutic intervention novel therapeutics phase 1 study prevent receptor retina blood vessel structure retinal neuron tumor growth

项目摘要

Retinopathy of prematurity (ROP), is a leading cause of vision impairment and blindness in children in the United States, due to pathological retinal neovascularization. We have discovered a novel angiogenic pathway that is involved in pathological neovascularization. This pathway is mediated by an endothelial nicotinic acetylcholine receptor (nAChR). The endothelial nAChR is a ligand-gated cationic channel that is activated by the endogenous signaling molecule, acetylcholine (ACh). Activation of this receptor induces endothelial cell mitogenesis, migration and tube formation and promotes angiogenesis. The pathway is upregulated by hypoxia, and by other angiogenic factors such as the vascular endothelial growth factor (VEGF). Accordingly, we propose the following Specific Aims to develop a novel therapy for ROP: 1. Characterize the endothelial nicotinic cholinergic pathway in the developing retina, and determine its role in normal vascularization. We hypothesize that normal development of the retina will not be adversely affected by pharmacological antagonism of the EC nAChRs. This hypothesis is based in part on the normal phenotype of the ¿7-nAChR deficient mouse. We will begin by determining, during normal development, the level of expression and localization of key elements of the nAChR pathway including the high affinity choline transporter, choline acetyltransferase, and the nAChR subunits. We will study EC from normal retinal vessels using laser capture microdissection and real time RT-PCR, in situ hybridization and immunohistochemistry. We will carefully assess vascular and neuronal development in the retina of the ¿7-nAChR deficient mouse. Finally, we will determine if pharmacological antagonism of nAChRs in the eye (comparing non-selective versus ¿7-nAChR selective antagonists) will adversely effect normal neuronal or vascular development. 2. Determine if excessive activation of this pathway contributes to retinal neovascularization in a murine model of ROP, using pharmacological and genetic knockdown of EC nAChRs. Using the methods described above, we will determine if retinal neovascularization is associated with increased retinal expression of any components of the nAChR pathway. We will determine if administration of the non-selective (mecamylamine) or ¿7-preferential (methyllycaconitine) nAChR antagonists suppress retinal neovascularization. The effect of nAChR antagonists on retinal neuronal function will be assessed by ERGs. ROP will be induced in ¿7- nAChR knockout mice and littermate controls to determine if signaling through ¿7- nAChRs contributes to retinal neovascularization. We will perform biochemical studies to assess the relationship between plasma and retinal levels of ACh, and correlate these levels to changes in retinal levels of vascular endothelial growth factor (VEGF), retinal vascularity and permeability.

早产儿视网膜病变（ROP）是美国儿童视力损害和失明的主要原因