Novel therapies to inhibit diabetic retinopathy

抑制糖尿病视网膜病变的新疗法

基本信息

批准号：
9037672
负责人：
Timothy S Kern
金额：
$ 161.77万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9037672
关键词：
Acute Adenylate Cyclase Adult Adverse effects Affect Age Agonist Aldehydes Animal Model Animals Basic Science Biochemistry Biomedical Engineering Blindness Blood capillaries Boston Callithrix Capillary Permeability Cells Characteristics Chemicals Clinical Research Collaborations Complex Coupled Developed Countries Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Disease Dose Dropout Drug Delivery Systems Drug Kinetics Electrophysiology (science)Emerging Technologies Eye Fibrates Figs - dietary Formulation G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Generations Glucose Goals Health High Pressure Liquid Chromatography Human Image Incubated Individual Intervention Ischemia Lead Lesion Liquid Chromatography Longitudinal Studies Mass Spectrum Analysis Medicine Methodology Methods Michigan Modeling Monitor Monoclonal Antibody R24 Mus National Eye Institute Nerve Degeneration Ophthalmology Optics Oxidative Stress Oxygen Pathogenesis Pathology Patients Pediatrics Permeability Pharmaceutical Preparations Pharmacodynamics Pharmacology Photoreceptors Physiological Primates Process Psychophysics Reperfusion Therapy Research Personnel Resolution Retina Retinal Retinal Diseases Retinal Neovascularization Rodent Rodent Model Route Selection Criteria Signal Pathway Staging Structure Subgroup Superoxides System Testing Therapeutic Therapeutic Effect Translating Translational Research Universities Vascular Permeabilities Vision Vision Disorders Visual Visual impairment Visual system structure Work aminoguanidine analytical method antagonist G base capillary diabetic drug candidate drug testing glycemic control imaging modality improved in vivo inhibitor/antagonist liquid chromatography mass spectrometry mouse model nanoparticle novel novel therapeutics prevent programs screening small molecule libraries tomography tool two-photon type I and type II diabetes type I diabetic

项目摘要

DESCRIPTION (provided by applicant): An interdisciplinary consortium of investigators from the Departments of Medicine, Pharmacology, Ophthalmology, Pediatrics and Biomedical Engineering at Case Western Reserve University, in collaboration with the University of Michigan, Harvard University, and Boston University proposes "to increase the pace at which basic science discoveries on disease mechanisms can be translated into therapies for complex visual system disorders and disease", a stated goal of the R24 National Eye Institute (NEI) Translational Research Program on Therapy for Visual Disorders. This scientific partnership will employ its diverse scientific expertise to characterize and test potential therapies for diabetic and other ischemic retinopathies in animal models by using a combination of cutting-edge physiological, chemical, analytical and imaging approaches. By identifying drugs with the capability to inhibit clinically important lesions of the early stages of diabetic retinopathy in animal models, we will accelerate their development before testing in humans. Improving drug delivery to the retina will also be a high priority. Conventional and emerging technologies together with high resolution imaging methods will be used noninvasively to assess various processes in the retina, and document the effect of therapies. Specific goals of this project are to: 1. Use retinylamine as the lead compound to develop and test the ability of other amino-containing compounds (derivatives from chemical libraries and chemicals synthesized especially for this project) to trap reactive aldehydes and/or inhibit superoxide generation by retinal cells incubated in glucose concentrations similar to those found in diabetes. A systems pharmacology approach will be employed to evaluate the ability of a second group of compounds consisting of agonists and antagonists of G protein-coupled receptors (GPCRs) to achieve similar therapeutic effects. 2. Test the best of these compounds singly and in combination for their ability to (a) inhibit lesions of the non-proliferative stage of diabetic retinopathy (increased capillary permeability and degeneration) in rodents and primates, and (b) inhibit capillary dropout and pre-retinal neovascularization in the oxygen- induced retinopathy model. 3. Assess the retention and efficacy of promising test drugs delivered to the retina by different routes compared to systemic delivery. An important criterion for selection of compounds for further study is that they do not impair visual function at the doses used. Ultimately, results of these interrelated aims will guide us in identifying the most promising therapeutics for further development in reducing retinopathy and vision loss in diabetic individuals.

描述（应用程序提供）：来自凯斯西部储备大学的医学，药理学，眼科，小儿科和生物医学工程的研究人员的跨学科联盟，与密歇根大学，哈佛大学和波士顿大学的提议合作，以增加对疾病的疾病和疾病的疾病机构的启示，以增加对疾病的疾病机构的空间，从而将其转化为疾病的疾病，从而将其转化为疾病的疾病，从而将其转化为疾病的疾病，从而将其转化为疾病的疾病，从而将其转化为疾病的疾病。 R24国家眼科研究所（NEI）关于视觉疾病治疗的翻译研究计划。这种科学的伙伴关系将利用其动物模型中的糖尿病和其他缺血性视网膜病的潜在疗法来表征和测试潜在的疗法，并结合尖端的生理学，化学，分析和成像方法。通过鉴定具有抑制动物模型糖尿病性视网膜病早期临床重要病变的能力的药物，我们将在人类测试之前加速其发育。改善对视网膜的药物输送也将是一个很高的优先事项。常规和新兴技术以及高分辨率成像方法将无创使用来评估视网膜中的各种过程，并记录疗法的影响。该项目的具体目标是：1。使用视网膜胺作为铅化合物来开发和测试其他含氨基氨基的化合物的能力（来自化学库和化学物质的衍生物，尤其是为该项目合成的化学物质）来阻止反应性醛和/或抑制与葡萄糖浓度相似的肠道浓度的视网膜细胞抑制超氧化细胞相似于尿贝氏菌群中的超级氧化物的能力。将采用系统药理学方法来评估由G蛋白偶联受体（GPCR）组成的第二组化合物的能力，以实现相似的治疗作用。 2。单独测试这些化合物中的最好的，并结合使用它们的能力，以（a）抑制啮齿动物和私人中糖尿病性视网膜病的非增殖阶段（增加毛细血管渗透性和退化）的病变，以及（b）抑制毛细血管粪便和新生视网膜的新生视网膜化剂量的模型。 3.与全身交付相比，通过不同的途径评估有前途的测试药物的保留率和有效性。选择进一步研究的化合物的重要标准是，它们不会以所使用的剂量损害视觉功能。最终，这些相互关联的目标的结果将指导我们确定最有希望的疗法，以进一步发展糖尿病患者的视网膜病变和视力丧失。