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: 8242218
• 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/8242218
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE (provided by applicant): This proposal involves training and mentoring students, fellows, and junior investigators in mouse pathobiology as well as performing preclinical efficacy of non-hormonal steroids in a mouse model of limb girdle muscular dystrophy 22B, rheumatoid arthritis and asthma. We will use state-of-the-art comprehensive preclinical assessments and evaluations of drug efficacy and toxicity in these mouse models. This proposal will help to train a pool of talented young scientists to pursue mouse model research and accelerate development of therapies for inflammatory diseases.

描述（由申请人提供）：候选人是一名兽医，拥有免疫学硕士和博士学位，对炎症性疾病转基因小鼠模型的生成和表型分析具有长期兴趣和专业知识。将罕见疾病的潜在治疗方法从实验室工作台转移到人类临床试验的一个主要障碍是获得人类疾病小鼠模型的“临床前”数据。目前在美国没有小鼠表型分析和药物筛选设施能够筛选大量药物或其他实验治疗剂，特别是用于罕见的炎性肌肉疾病。候选人已经在儿童国家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，制定标准操作程序，以定义临床前终点，用于评估神经肌肉疾病小鼠模型的治疗干预。该奖项将帮助建立1）为来自全国各地的初级教师，博士后研究员，研究生，技术人员和学员提供结构化的培训和指导计划，重点是小鼠模型中肌肉疾病的分子和功能病理学;和2）帮助候选人发展和扩展他的研究和培训，以评估现代药物在这些罕见的模型中的治疗效果。人类疾病。糖皮质激素（GC）已成功地用于治疗许多急性和慢性炎症性疾病的几十年。这些药物对多种疾病非常有效的主要原因是它们能够同时阻断多个阶段的炎症级联反应。类固醇处方的主要局限性在于，这些所需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、青光眼以及长期使用的许多其他副作用。因此，迫切需要开发具有标准GC的抗炎效力但副作用降低的化合物。已经提出，有益作用是由于GC-糖皮质激素受体（GR）介导的细胞质中的反式抑制（NF-κ B抑制）活性，而副作用（代谢和激素）被认为主要是由通过细胞核中的GC反应元件的反式激活介导的。因此，优先诱导GR的反式阻遏而非反式激活功能的配体对于治疗慢性炎性病症是理想的。我们的研究小组与Validus Bioburma（VBP）合作，已经鉴定并测试了几种GC类似物，它们通过抑制骨骼肌细胞中的NF-κ B活性来有效地阻断炎症。在这个提议中，我们假设这些新型非激素类固醇显着减少炎症和改善肌肉功能，关节炎和哮喘表型，而不会引起显着的不良反应。目标1.使用充分表征的功能、行为、免疫学、成像和组织学测定来测试VBP-3和VBP 15在LGMD 2B小鼠模型中的功效和毒性。目标2。使用临床、组织学和成像测定评估VBP-3和VBP 15在该关节炎小鼠模型中的功效和毒性。目标3.使用免疫学和组织学终点系统地评价VBP 3和VBP 15的功效。研究设计：所有目的均使用小鼠模型和正常小鼠品系。相关性：这些实验可以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，还用于关节炎，哮喘和几种人类免疫和炎症疾病。该计划将帮助候选人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针对炎症性疾病的特效药。 公共卫生相关性（由申请人提供）：该提案涉及在小鼠病理生物学方面培训和指导学生、研究员和初级研究人员，以及在肢带型肌营养不良症22 B、类风湿性关节炎和哮喘的小鼠模型中进行非激素类固醇的临床前疗效。我们将在这些小鼠模型中使用最先进的综合临床前评估和药物疗效和毒性评价。这项提议将有助于培养一批有才华的年轻科学家，从事小鼠模型研究，并加速炎症性疾病疗法的开发。