Targeted Pharmacological Chaperones for Neurological Diseases

神经系统疾病的靶向药理学伴侣

• 批准号: 8903606
• 负责人: JOHN J NALEWAY
• 金额: $ 22.46万
• 依托单位: MARKER GENE TECHNOLOGIES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903606
• 关键词: Active Sites; Affect; Ally; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Antibodies; Area; Azides; Bacterial Infections; Basic Science; Binding; Biological; Biological Assay; Biological Monitoring; Biotechnology; Cell Culture System; Cell Culture Techniques; Cell Fraction; Cell Line; Cells; Chemicals; Chemistry; Chlamydia; Cholera; Clinical Treatment; Coculture Techniques; Collaborations; Cysteine; Cytolysis; Data; Degenerative Disorder; Development; Disease; Drug Targeting; Drug toxicity; Endoplasmic Reticulum; Enzyme-Linked Immunosorbent Assay; Enzymes; Exhibits; Fluorescence Microscopy; Fluorogenic Substrate; Gaucher Disease; Genes; Glioblastoma; Goals; Golgi Apparatus; High Pressure Liquid Chromatography; Human; Human Cell Line; In Vitro; Individual; Infection; Intervention; Label; Laboratories; Lead; Life; Lysosomal Storage Diseases; Measurement; Medical; Medicine; Methods; Miglustat; Modeling; Modification; Molecular Chaperones; Myeloid Leukemia; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Oculocerebrorenal Syndrome; Organelles; Parkinson Disease; Patients; Peptides; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Phospholipids; Plants; Preparation; Protein Secretion; Proteins; Protocols documentation; Radiolabeled; Research; Running; Side; Small Business Innovation Research Grant; Staining method; Stains; Sulfhydryl Compounds; System; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Virus Diseases; Work; Yeasts; analog; analytical tool; chemical standard; drug discovery; drug efficacy; efficacy testing; enzyme activity; enzyme replacement therapy; glucosidase; glucosylceramidase; improved; in vitro Assay; in vivo; inhibitor/antagonist; innovation; meetings; mutant; nervous system disorder; novel; novel therapeutics; pre-clinical; protein degradation; protein folding; protein misfolding; protein transport; public health relevance; radiotracer; research study; screening; small molecule; success; tissue culture; tool; uptake

 DESCRIPTION (provided by applicant): This Small Business Innovation Research Phase I project aims to develop new targeted pharmacological chaperones capable of modulating enzyme degradation in the Golgi apparatus and Endoplasmic Reticulum (ER) of living cells and tissues. If successful, the proposed research will provide breakthroughs needed to advance the discovery of promising new therapies and modulating drugs for neurodegenerative disorders including lysosomal storage diseases, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), myeloid leukemia, glioblastoma, Type 2 diabetes, Lowe syndrome and allied degenerative diseases and medical conditions involving protein misfolding. In Phase I of this project, Marker Gene Technologies, Inc. will establish the feasibility of the technology by preparing new targeted pharmacological chaperones, demonstrating improved loading and localized accumulation in the Golgi and ER and demonstrating efficacy for increasing lysosomal enzyme activity in living cells that are of disease origin in comparison to those from normal controls. In Phase II, these and additional new targeted drug conjugates will be evaluated in vitro and in vivo for their ability to affect specific and localized induction of tese enzymes in living cells as well as alleviate unwanted protein degradation or improve protein trafficking in a cell- or tissue- specific manner using a variety of delivery methods. These new pharmacological chaperones and the resulting targeting systems will provide innovative methods to modulate Golgi and ER organelle function and thereby screen for the influence of secondary drug or protein administration, affect intracellular trafficking of proteins or improve transport or secretion of proteins, making them useful analytical tools for drug discovery and basic research in a variety of significant medical applications. Our very preliminary results indicate the proposed methods have the potential to increase intracellular loading and targeting of pharmacological chaperones in human cell lines from patients with Gaucher disease, thereby providing a new tool to the arsenal of available therapeutics for clinical treatment of neurodegenerative disorders.

 描述（由申请人提供）：该小型企业创新研究I期项目旨在开发能够调节活细胞和组织的高尔基体和内质网（ER）中酶降解的新型靶向药理学分子伴侣。如果成功，拟议的研究将提供突破，以推进发现有前途的新疗法和神经退行性疾病的调节药物，包括溶酶体贮积病，阿尔茨海默病（AD），肌萎缩侧索硬化症（ALS），帕金森病（PD），骨髓性白血病，胶质母细胞瘤，2型糖尿病，Lowe综合征和相关的退行性疾病和涉及蛋白质错误折叠的医疗条件。在该项目的第一阶段，Marker Gene Technologies，Inc.将通过制备新的靶向药理学分子伴侣来确定该技术的可行性，证明高尔基体和ER中的负载和局部积累得到改善，并证明与来自正常对照的那些相比，在疾病来源的活细胞中提高溶酶体酶活性的功效。在II期，将在体外和体内评价这些和另外的新靶向药物缀合物影响活细胞中tese酶的特异性和局部诱导以及使用多种递送方法以细胞或组织特异性方式减轻不需要的蛋白质降解或改善蛋白质运输的能力。这些新的药理学伴侣和由此产生的靶向系统将提供创新的方法来调节高尔基体和ER细胞器功能，从而筛选二级药物或蛋白质给药的影响，影响蛋白质的细胞内运输或改善蛋白质的运输或分泌，使其成为药物发现和基础研究的有用分析工具，在各种重要的医学应用。我们非常初步的结果表明，所提出的方法有可能增加戈谢病患者的人细胞系中药理学分子伴侣的细胞内负载和靶向，从而为神经退行性疾病的临床治疗提供了一种新的工具。