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

• 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
• 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' 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

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.

摘要 来自药理学和眼科学系的跨学科研究者联盟 在凯斯西储大学，克利夫兰路易斯斯托克斯退伍军人医疗中心，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 天才的目标实验室公司，建议“加快基础科学发现的步伐， 疾病机制可以转化为复杂的视觉系统障碍和疾病的治疗”， R24国家眼科研究所视觉障碍治疗转化研究计划。这一科学 该合作伙伴将利用其多样化的专业知识，在动物模型中评估视网膜疾病的潜在疗法 通过使用尖端的系统药理学范例。通过筛选G蛋白偶联 受体（GPCR）激动剂/拮抗剂药物（调节剂），因为它们在动物中预防视网膜病变的能力 模型的各种杆和锥感光细胞视网膜病变，我们将确定合适的候选人，为未来 在人类身上测试。高分辨率成像方法和转录分析等方法将 用于监测这些联合治疗的疗效和安全性。该项目的目标是：目标1。 在小鼠中测试GPCR激动剂/拮抗剂的组合在保护免受光诱导的免疫损伤中的功效。 视网膜损伤和自发性快速或缓慢进展的视锥细胞变性。目标2. 药理学和遗传学验证了所鉴定的GPCR的参与和特异性以及它们的精确表达。 使用T4溶酶体（T4 L）融合到其信号传导结构域中的敲入小鼠进行亚细胞定位， 我们研制的抗T4 L抗体我们还将使用FAST系统， (from失活至过表达）以在单个小鼠模型中进行工程化。目标3.评估其有效性 GPCR疗法在犬视杆-视锥视网膜病变模型中的应用。目标4。扩大受体调节剂的范围， 包括治疗性抗体。实现这些相互关联的目标将指导我们发展更成功的 治疗患有无法治愈的致盲疾病的人。