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MECHANISM OF ACTION OF HALOFUGINONE AS A NOVEL THERAPEUTIC

卤常酮作为新型治疗药物的作用机制

基本信息

批准号：
7767129
负责人：
MALCOLM R. WHITMAN
金额：
$ 37.29万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7767129
关键词：
Accounting Acids Amino Acids Amino Acyl-tRNA Synthetases Animal Disease Models Animal Model Autoimmune Process Autoimmunity Biological Biological Assay Cells Chronic Detection Diabetic Nephropathy Disease Enzyme Inhibition Enzymes Fibrosis GCN2 protein kinase Halofuginone Immune In Vitro Inflammatory Investigation Kinetics Knowledge Link Mediating Mediator of activation protein Metabolic Molecular Target Multiple Sclerosis Muscular Dystrophies Pathogenesis Pathology Pathway interactions Phenotype Plasma Population Prevention Reporting Scleroderma Signal Pathway Signal Transduction Specificity Starvation T-Lymphocyte Testing Therapeutic Therapeutic Effect Tissues angiogenesis base cell behavior cell type effective therapy enzyme activity glutamyl-prolyl-tRNA synthetase in vitro activity in vivo mouse model novel novel strategies novel therapeutics proline-tRNA public health relevance research study response small molecule uptake

项目摘要

DESCRIPTION (provided by applicant): The use of small molecules to manipulate metabolic function in vivo has emerged as an important new approach to therapy for a wide range of disease pathologies. The amino acid starvation response (AAR) is a signaling pathway that controls a variety metabolic and cytoprotective functions in response to the restriction of amino acid availability. In our preliminary experiments we have found that halofuginone, a small molecule with efficacy in a variety of animal disease models involving fibrosis and angiogenesis, is a potent and specific activator of the AAR. We have also found that halofuginone activates the AAR through a novel mechanism, and acts independently of the best characterized mediator of AAR signaling. Through this novel signaling mechanism, HF regulates a variety of previously described cell behaviors associated with disease pathology or pathogenesis. We have also identified a novel, specific effect of HF on the differentiation in vitro and in vivo pro-inflammatory T-cells. HF alters T-cell populations in vivo in a way predicted by its effects in vitro. HF reduces inflammatory pathology in a mouse model of autoimmunity, indicating that HF has strong potential as a new class of therapeutic for autoimmune and chronic inflammatory disease. These observations open an exciting new set of opportunities for understanding how HF, and other small molecules with similar molecular targets, may have new and unexpected uses for the treatment of pathology associated with chronic inflammatory disease. PUBLIC HEALTH RELEVANCE: We have identified a small molecule that in animal models is effective for the treatment of pathological tissue changes associated with a wide range of diseases, including multiple sclerosis, scleroderma, muscular dystrophy, and diabetic nephropathy. We plan to characterize the mechanism of action of this molecule as a new class of disease therapeutic.

描述（由申请人提供）：使用小分子来操纵体内代谢功能已成为治疗多种疾病病理的重要新方法。氨基酸饥饿反应（AAR）是一种响应于氨基酸可利用性的限制而控制多种代谢和细胞保护功能的信号通路。在我们的初步实验中，我们已经发现，常山酮，一种小分子，在涉及纤维化和血管生成的各种动物疾病模型中具有功效，是AAR的有效和特异性激活剂。我们还发现，卤夫酮激活AAR通过一种新的机制，并独立的AAR信号传导的最佳表征介质。通过这种新的信号传导机制，HF调节多种先前描述的与疾病病理或发病机制相关的细胞行为。我们还确定了一种新的，具体的影响，HF的分化在体外和体内促炎T细胞。HF以其体外效应预测的方式改变体内T细胞群。HF减少了自身免疫小鼠模型中的炎症病理学，表明HF具有作为自身免疫和慢性炎症疾病的新型治疗剂的强大潜力。这些观察结果为理解HF和其他具有类似分子靶点的小分子如何在治疗慢性炎症性疾病相关病理学方面具有新的和意想不到的用途提供了一系列令人兴奋的新机会。公共卫生关系：我们已经鉴定了一种小分子，其在动物模型中有效治疗与多种疾病相关的病理组织变化，包括多发性硬化症、硬皮病、肌营养不良和糖尿病肾病。我们计划将这种分子的作用机制描述为一类新的疾病治疗药物。