Regulation of vitamin A metabolism in the eye

眼内维生素A代谢的调节

基本信息

批准号：
10320919
负责人：
Marcin Bernard Golczak
金额：
$ 44.66万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320919
关键词：
11 cis Retinal Acute Adolescent Affect Affinity Age related macular degeneration All-Trans-Retinol Animal Model Binding Binding Proteins Biochemical Biochemical Reaction Biological Biological Assay Biological Availability Biophysics Blood Blood-Retinal Barrier Cells Cellular Retinol Binding Protein Characteristics Chronic Clinical Clinical Trials Data Development Disease Drug Kinetics Drug or chemical Tissue Distribution Electroretinography Equilibrium Etiology Event Exposure to Eye FDA approved G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Genetic Goals Health Heart Homeostasis Imaging Techniques Impairment Inherited Investigational Therapies Lasers Lead Ligands Light Lighting Link Macular degeneration Medical Metabolism Methodology Methods Modeling Monitor Mus Ophthalmoscopy Optical Coherence Tomography Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacological Treatment Pharmacology Phenotype Photons Photoreceptors Physical condensation Physiological Prevention Prevention therapy Process Property Proteins Recycling Regulation Research Retina Retinal Degeneration Retinal Diseases Retinaldehyde Retinoids Retinol Binding Proteins Rhodopsin Scaffolding Protein Scanning Series Solid Stargardt&apos s disease Stream Technology Testing Therapeutic Therapeutic Agents Therapeutic Effect Vision Vitamin A advanced analytics analytical tool antagonist base cellular targeting chemical property chromophore cytotoxicity drug candidate drug discovery effective therapy experimental study high throughput screening human model improved in vivo in vivo evaluation insight mouse model non-invasive imaging novel novel drug class novel therapeutics photoactivation prevent retinal damage small molecule stem systemic toxicity therapeutic target two photon microscopy uptake visual cycle vitamin metabolism

项目摘要

ABSTRACT: In a healthy eye, the proper homeostasis of vitamin A (all-trans-retinol, atROL) supports visual function under a variety of lighting conditions. However, certain environmental insults in combination with an unfavorable genetic background can overcome the adaptive capabilities of ocular retinoid metabolism and compromise retinal function. The clinical examples are Stargardt disease, an inherited form of juvenile macular degeneration and Age-related macular degeneration (AMD), in which an imbalance in retinoid metabolism is an important etiologic factor. Despite intensive studies, FDA approved treatments for inherited or acquired degenerative retinal diseases are very limited. In this project, we propose to expand potential treatment options for the retinal degenerative diseases by developing a safe and effective method of controlling the ocular flux of retinoids by targeting vitamin A binding proteins. To obtain insight into the potential therapeutic applications of this approach, we propose comprehensive studies that combine diverse biochemical, biophysical, and physiological methods aimed at developing candidate drugs and assessing their biological effects in animal models of human retinal degenerative diseases. To achieve these goals, we propose three specific aims. In Aim 1, we will utilize high-throughput screening (HTS) technology to identify small-molecule antagonists of cellular retinol-binding protein (CRBP1). We will select lead compounds and characterize their binding properties. We will also validate their biological activity in a cell-based secondary assay. Ultimately, we will pre-select the first-in-class drug candidates that allow for the pharmaceutical manipulation of retinoid metabolism. In Aim 2, the therapeutic potential of CRBP1 ligands will be assessed by evaluating changes in biochemical and pathophysiological processes in the retinas in vivo. The results of experimental therapies will be monitored by electroretinograms, non-invasive imaging techniques, including optical coherence tomography, scanning laser ophthalmoscopy, and two-photon microscopy, whereas ocular retinoid metabolism will be examined with advanced analytical tools. Ultimately, we will link the biochemical properties of CRBP1 antagonists with their therapeutic effects, and thus provide solid proof-of-concept data that could be further developed into initial clinical trials. In Aim 3, we will combine the structural information about the mode of non-retinoid ligands interaction with CRBP1 and methods of medicinal chemistry to rationally improve pharmacodynamic properties of drug candidates. We will also determine pharmacokinetics of the selected drug candidates in the context of their ability to cross the blood/retina barrier. The completion of these experiments will identify the chemical properties that provide the best efficacy profile for the lead compounds. Together, our studies will contribute a novel mechanism-based therapeutic strategy for blinding eye conditions and first-in-class drug candidates pre-tested in vivo that will expand treatment options for millions of patients affected by retinal degenerative diseases.

抽象的：在健康的眼中，维生素A（全反元素，Atrol）的适当稳态支持在A下的视觉功能各种照明条件。但是，某些环境侮辱与不利遗传背景可以克服眼类维生素代谢和妥协的适应能力视网膜功能。临床例子是Stargardt疾病，这是一种遗传的少年黄斑形式变性和与年龄相关的黄斑变性（AMD），其中类维生素性代谢失衡为一个重要的病因因素。尽管进行了深入研究，但FDA还是批准了继承或获得的治疗方法退化性视网膜疾病非常有限。在这个项目中，我们建议扩大潜在的治疗选择通过开发一种安全有效的控制眼通量的方法，用于视网膜退行性疾病类视视视网想通过靶向维生素A结合蛋白。了解有关潜在的治疗应用的见解这种方法，我们提出了结合多种生化，生物物理和旨在开发候选药物并评估动物的生物学作用的生理方法人类视网膜退行性疾病的模型。为了实现这些目标，我们提出了三个具体目标。在AIM 1中，我们将使用高通量筛查（HTS）鉴定细胞视黄醇结合蛋白（CRBP1）的小分子拮抗剂的技术。我们将选择铅化合物并表征其结合特性。我们还将验证它们在基于细胞的次要测定。最终，我们将预选允许的第一类候选者类维生素性代谢的药物操纵。在AIM 2中，CRBP1配体的治疗潜力将通过评估体内视网膜中生化和病理生理过程的变化来评估。实验疗法的结果将通过电子图，非侵入性成像来监测技术，包括光学相干断层扫描，扫描激光眼镜检查和两光子显微镜检查，而眼类维生素的代谢将使用高级分析工具进行检查。最终，我们将将CRBP1拮抗剂的生化特性与其治疗作用联系起来，从而提供可靠的概念验证数据可以进一步发展为初始临床试验。在AIM 3中，我们将结合有关非类交配体与CRBP1相互作用的模式的结构信息以及药物化学以合理提高候选药物的药效学特性。我们也会确定所选药物候选物的药代动力学在其越过的能力下血/视网膜屏障。这些实验的完成将确定提供的化学特性铅化合物的最佳功效概况。总之，我们的研究将为盲目的眼睛条件做出新的基于机制的治疗策略和一流的候选药物在体内预先测试，将扩大数百万患者的治疗选择受视网膜退行性疾病的影响。