Preclinical drug trial in mouse models of inflammation

炎症小鼠模型的临床前药物试验

• 批准号: 8690993
• 负责人: KANNEBOYINA NAGARAJU
• 金额: $ 10.62万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690993
• 关键词: Acute; Adhesions; Adverse effects; Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Asthma; Atrophic condition of skin; Award; Behavioral; Biological Assay; CD4 Positive T Lymphocytes; Cell Nucleus; Cell membrane; Chemotaxis; Child; Chronic; Clinical; Clinical Data; Clinical Trials; Collaborations; Collagen Arthritis; Competitive Binding; Country; Cushing Syndrome; Cytoplasm; Cytoskeletal Modeling; Data; Development; Diabetes Mellitus; Disease; Disease model; Doctor of Philosophy; Drug toxicity; Duchenne muscular dystrophy; Dystrophin; Evaluation; Faculty; Functional disorder; Future; Gene Targeting; Glaucoma; Glucocorticoid Receptor; Glucocorticoids; Hormonal; Human; Image; Immune; Immunology; In Vitro; Inflammation; Inflammatory; International; Joints; Laboratories; Lead; Leukocytes; Ligands; Limb-Girdle Muscular Dystrophies; Lipid Peroxidation; Lung; Lupus; Mediating; Medical center; Mentors; Metabolic; Modeling; Molecular; Mouse Strains; Mus; Muscle Fibers; Muscle function; Muscular Dystrophies; Myopathy; Myositis; NF-kappa B; Neuromuscular Diseases; Osteoporosis; Outcome; Pathogenesis; Pathway interactions; Patients; Peptic Ulcer; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Play; Postdoctoral Fellow; Preclinical Drug Evaluation; Procedures; Psychotic Disorders; Rare Diseases; Research; Research Design; Research Personnel; Research Training; Response Elements; Rheumatoid Arthritis; Role; Scientist; Skeletal Muscle; Staging; Steroids; Structure; Students; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Training; Transactivation; Transgenic Mice; Treatment Efficacy; Universities; Veterinarians; Washington; analog; base; defined contribution; drug development; drug efficacy; drug testing; efficacy testing; eosinophil; graduate student; human disease; improved; in vivo; interest; mdx mouse; migration; mouse model; novel; pre-clinical; preclinical efficacy; programs; receptor binding; research study; screening; therapy development

DESCRIPTION (provided by applicant): The Candidate, a veterinarian with Master's and PhD degrees in immunology, has a long-standing interest and expertise in generating and phenotyping transgenic mouse models for inflammatory diseases. A major stumbling block in moving potential therapeutic approaches for rare diseases from the laboratory bench to human clinical trials involves obtaining "pre-clinical" data in mouse models of human disease. There is currently no mouse phenotyping and drug screening facility in the USA that is capable of screening large numbers of drugs or other experimental therapeutics particularly for rare inflammatory muscle diseases. The Candidate has established a state-of-the-art murine phenotyping and drug testing facility for neuromuscular disease mouse models at the Children's National Medical Center and is currently leading international efforts to develop standard operating procedures to define preclinical endpoints for evaluating therapeutic interventions in murine models of neuromuscular disorders. This award will help establish 1) a structured training and mentoring program for junior faculty, post-doctoral fellows, graduate students, technicians, and trainees from around the country that is focused on the molecular and functional pathobiology of muscle diseases in mouse models; and 2) help the Candidate develop and extend his research and training related to evaluating the therapeutic efficacy of modern drugs in these models of rare human diseases. Glucocorticoids (GCs) have been successfully used in the treatment of many acute and chronic inflammatory diseases for several decades. The main reason that these drugs are very effective in multiple disease conditions is due to their ability to simultaneously block the inflammatory cascade at multiple stages. The major limitation of steroid prescription is that these desired anti-inflammatory effects are generally accompanied by drastic side effects such as diabetes mellitus, peptic ulcer, Cushing's syndrome, osteoporosis, skin atrophy, psychosis, glaucoma, and many others upon chronic use. Therefore there is an urgent need for the development of compounds with the anti- inflammatory potency of standard GCs but with reduced side effects. It has been proposed that beneficial effects are due to GC-glucocorticoid receptor (GR) mediated transrepressive (NF-kB inhibition) activities in cytoplasm and side effects (metabolic and hormonal) are thought to be predominantly mediated by transactivation via GC response elements in the nucleus. Thus, ligands that preferentially induce the transrepression and not transactivation function of the GR are ideal for treating chronic inflammatory conditions. Our group, in collaboration with Validus Biopharma (VBP), has identified and tested several GC analogues that efficiently block inflammation by inhibiting NF-kB activity in skeletal muscle cells. In this proposal we hypothesize that these novel non-hormonal steroids significantly reduce inflammation and improve muscle function, arthritis and asthma phenotypes without causing significant adverse effects. Aim.1. Test efficacy and toxicity VBP-3 and VBP15 in mouse model of LGMD2B using well-characterized functional, behavioral, immunological, imaging, and histological assays. Aim.2. Assess the efficacy and toxicity of VBP-3 and VBP15 in this arthritis mouse model using clinical, histological and imaging assays. Aim 3. Evaluate efficacy of VBP3 and VBP15 systematically using immunological and histological endpoints. Study Design: All aims use murine models and normal mouse strains. Relevance: These experiments could provide the basis for future human clinical trials with non-hormonal steroids, not only for dystrophies but also for arthritis, asthma and several human immune and inflammatory diseases. This program will help the Candidate to train and develop scientists interested in drug development in academic settings. These efforts in the long term will help us to develop specific drugs for inflammatory diseases.

应聘者描述(申请人提供)：应聘者是一名兽医，拥有免疫学硕士和博士学位，对构建炎症性疾病转基因小鼠模型和表型具有长期的兴趣和专业知识。将罕见疾病的潜在治疗方法从实验室转移到人类临床试验的一个主要绊脚石是在人类疾病的小鼠模型中获得“临床前”数据。目前，美国还没有小鼠表型和药物筛选设施，能够筛选大量的药物或其他实验性疗法，特别是针对罕见的炎症性肌肉疾病。这位候选人已经在国家儿童医学中心建立了最先进的神经肌肉疾病小鼠模型的小鼠表型和药物测试设施，目前正在领导国际努力，开发标准操作程序，以确定临床前终点，以评估神经肌肉疾病小鼠模型的治疗干预。该奖项将帮助1)为来自全国各地的初级教师、博士后研究员、研究生、技术员和受训人员建立一个系统的培训和指导计划，重点是小鼠模型中肌肉疾病的分子和功能病理生物学；以及2)帮助候选人发展和扩展与评估现代药物在这些罕见人类疾病模型中的治疗效果有关的研究和培训。糖皮质激素(GCs)几十年来已成功应用于多种急慢性炎症性疾病的治疗。这些药物在多种疾病条件下非常有效的主要原因是它们能够在多个阶段同时阻止炎症级联。类固醇处方的主要局限性是，这些预期的抗炎作用通常伴随着严重的副作用，如糖尿病、消化性溃疡、库欣综合征、骨质疏松症、皮肤萎缩、精神病、青光眼和许多其他长期使用的副作用。因此，迫切需要开发具有标准GC抗炎效力但副作用减少的化合物。已有研究认为，其有益作用是由于GC-糖皮质激素受体(GR)介导的胞浆反式抑制(核因子-kB抑制)活性，而副作用(代谢和激素)主要是通过核内GC反应元件介导的反式激活。因此，优先诱导GR反式抑制而非反式激活功能的配体是治疗慢性炎症性疾病的理想选择。我们的团队与Validus Biophma(VBP)合作，已经确定并测试了几种GC类似物，它们通过抑制骨骼肌细胞中的NF-kB活性而有效地阻止炎症。在这项建议中，我们假设这些新的非激素类固醇显著减少炎症，改善肌肉功能，关节炎和哮喘的表型，而不会引起显著的不良反应。目标1.使用功能、行为、免疫学、影像和组织学检测方法，测试VBP-3和VBP15在LGMD2B小鼠模型中的有效性和毒性。目的：2.通过临床、组织学和影像分析评估VBP-3和VBP15在该关节炎小鼠模型中的疗效和毒性。目的3.从免疫学和组织学终点系统评价VBP3和VBP15的疗效。研究设计：所有研究对象均采用小鼠模型和正常小鼠品系。相关性：这些实验可能为未来非激素类固醇的人类临床试验提供基础，不仅用于营养不良，而且还用于关节炎、哮喘和几种人类免疫和炎症性疾病。该计划将帮助应聘者在学术环境中培养和发展对药物开发感兴趣的科学家。从长远来看，这些努力将有助于我们开发治疗炎症性疾病的特效药。