Use of systems pharmacology to prevent rod and cone photoreceptor degeneration

利用系统药理学预防视杆细胞和视锥细胞光感受器变性

基本信息

批准号：
9554184
负责人：
Krzysztof Palczewski
金额：
$ 42万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2017-07-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9554184
关键词：
Ablation Adenylate Cyclase Affect Age related macular degeneration Agonist Animal Model Antibodies Avastin Basic Science Biochemical Process Blindness Canis familiaris Cell Death Cell Survival Cells Clinic Clinical Treatment Clinical Trials Combined Modality Therapy Complex Cone Cyclic AMP Data Development Disease Dose Drug Industry Drug Kinetics Drug effect disorder Dysplasia Effectiveness Engineering Ensure Evaluation Event Exhibits Exudative age-related macular degeneration Eye FDA approved Foundations Future G-Protein-Coupled Receptors Gene Expression Genetic Genetic Transcription Goals Human Institutes Intervention Knock-in Mouse Knock-out Laboratories Light Link Lucentis Lysosomes Medical Medical center Messenger RNA Michigan MicroRNAs Modeling Monitor Monoclonal Antibodies Monoclonal Antibody R24 Mus National Eye Institute Ocular Pathology Ophthalmology Outcome Partner in relationship Pathology Pathway interactions Pharmaceutical Preparations Pharmacodynamics Pharmacological Treatment Pharmacology Pharmacotherapy Photoreceptors Physiology Production Property Proteins Research Research Personnel Retina Retinal Retinal Cone Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Safety Second Messenger Systems Secondary to Signal Pathway Signal Transduction Site Specificity Stargardt&apos s disease Structure Structure of retinal pigment epithelium System Technology Testing Therapeutic Therapeutic Agents Therapeutic Intervention Therapeutic Monoclonal Antibodies Therapeutic antibodies Toxic effect Translating Treatment Efficacy Universities Untranslated RNA Validation Vertebrate Photoreceptors Vision Disorders Visual impairment Visual system structure Washington analytical method antagonist G base bevacizumab biological systems combat design drug candidate environmental stressor flexibility high resolution imaging imaging modality improved interest mouse model next generation sequencing novel novel strategies overexpression photoreceptor degeneration prevent protective effect ranibizumab receptor research clinical testing restoration retinal damage retinal rods screening small molecule success successful intervention targeted treatment transcriptome translational research program

项目摘要

ABSTRACT An interdisciplinary consortium of investigators from the Departments of Pharmacology and Ophthalmology at Case Western Reserve University, the Cleveland Louis Stokes VA Medical Center, the Cole Eye Institute at Cleveland Clinic Foundation, Washington University, Michigan State University, Johns Hopkins University and ingenious Targeting Laboratory, Inc., proposes "to increase the pace at which basic science discoveries of disease mechanisms can be translated into therapies for complex visual system disorders and disease", a goal of the R24 National Eye Institute Translational Research Program on Therapy for Visual Disorders. This scientific partnership will employ its diverse expertise to evaluate potential therapies for retinal diseases in animal models by using a cutting-edge systems pharmacology paradigm. By screening a combination of G protein-coupled receptor (GPCR) agonist/antagonist drugs (modulators) for their ability to prevent retinal pathology in animal models of various rod and cone photoreceptor cell retinopathies, we will identify suitable candidates for future testing in humans. High resolution imaging methods and transcriptional analysis among other approaches will be used to monitor the efficacy and safety of these combination therapies. The goals of this project are: Aim 1. Test in mice the efficacy of a combination of GPCR agonists/antagonists in protecting against light-induced retinal damage and with either spontaneous rapid or slowly-progressing cone degeneration. Aim 2. Pharmacologically and genetically validate the involvement and specificity of identified GPCRs and their precise subcellular localization using knockin mice with T4 lysosome (T4L) fused into their signaling domains and an antibody we developed against T4L. We also will use the FAST system that allows various genetic outcomes (from inactivation to overexpression) to be engineered in a single mouse model. Aim 3. Assess the effectiveness of GPCR therapy in a canine rod-cone retinopathy model. Aim 4. Expand the range of receptor modulators to include therapeutic antibodies. Fulfilling these interrelated aims will direct our development of more successful therapies for people with incurable blinding diseases.

抽象的来自药理学和眼科部门的研究人员的跨学科联盟在Case Western Reserve University，Cleveland Louis Stokes VA医疗中心，科尔眼科研究所克利夫兰临床基金会，华盛顿大学，密歇根州立大学，约翰·霍普金斯大学和巧妙的目标实验室公司提议“提高基础科学发现的步伐疾病机制可以转化为复杂视觉系统疾病和疾病的疗法”，一个目标 R24国家眼科研究所的视觉疾病治疗研究计划。这个科学合作伙伴关系将利用其多样化的专业知识来评估动物模型中视网膜疾病的潜在疗法通过使用尖端的系统药理学范式。通过筛选G蛋白耦合的组合受体（GPCR）激动剂/拮抗剂（调节剂）预防动物视网膜病理学的能力各种杆和锥形感光细胞视网膜病变的模型，我们将确定适合将来的候选者在人类中进行测试。高分辨率成像方法和其他方法的转录分析将用于监测这些组合疗法的功效和安全性。该项目的目标是：目标1。在小鼠中测试GPCR激动剂/拮抗剂在保护光引起的疗效视网膜损伤，并具有自发的快速或缓慢产生的锥变性。目标2。从药理和遗传上验证已鉴定的GPCR的参与和特异性及其精确性使用T4溶酶体（T4L）融合到其信号域的T4溶酶体（T4L）的敲蛋白小鼠的亚细胞定位和一个我们针对T4L开发的抗体。我们还将使用允许各种遗传结果的快速系统（从灭活到过表达）将在单个鼠标模型中进行设计。目标3。评估有效性在犬杆锥视网膜病变模型中的GPCR治疗。目标4。将受体调节剂的范围扩展到包括治疗性抗体。实现这些相互关联的目标将指导我们的发展更成功患有无法治愈的盲目疾病的人的疗法。