Preclinical drug trial in mouse models of inflammation

描述（由申请人提供）：该候选人是一名兽医，拥有免疫学硕士和博士学位，长期以来一直对炎症性疾病的转基因小鼠模型的产生和表型分析感兴趣和专业知识。将罕见疾病的潜在治疗方法从实验室工作台转移到人体临床试验的一个主要障碍涉及在人类疾病的小鼠模型中获取“临床前”数据。目前，在美国没有能够筛选大量药物或其他实验性治疗方法的小鼠表型和药物筛选设施，特别是针对罕见的炎症性肌肉疾病。该候选人已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，以确定评估神经肌肉疾病小鼠模型治疗干预的临床前终点。该奖项将帮助建立一个结构化的培训和指导计划，面向来自全国各地的初级教师、博士后、研究生、技术人员和学员，重点关注小鼠模型中肌肉疾病的分子和功能病理生物学；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相关的研究和培训。几十年来，糖皮质激素（GCs）已成功地用于治疗许多急慢性炎症性疾病。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断炎症级联反应。类固醇处方的主要限制是，这些期望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。因此，迫切需要开发具有标准gc抗炎效力但副作用较小的化合物。有人提出，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抑制（NF-kB抑制）活动，而副作用（代谢和激素）被认为主要是通过核中GC反应元件的反激活介导的。因此，优先诱导GR转抑制而非转激活功能的配体是治疗慢性炎症的理想选择。我们的团队与Validus Biopharma （VBP）合作，已经鉴定并测试了几种GC类似物，这些类似物通过抑制骨骼肌细胞中NF-kB的活性来有效阻断炎症。在这项提议中，我们假设这些新的非激素类固醇可以显著减少炎症，改善肌肉功能，关节炎和哮喘表型，而不会引起明显的不良反应。Aim.1。通过功能、行为、免疫学、影像学和组织学分析，测试vbp3和VBP15在LGMD2B小鼠模型中的功效和毒性。Aim.2。通过临床、组织学和影像学检查评估vbp3和VBP15在关节炎小鼠模型中的疗效和毒性。目标3。采用免疫学和组织学指标系统评价VBP3和VBP15的疗效。研究设计：所有目的均采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体临床试验提供基础，不仅可以用于营养不良症，还可以用于关节炎、哮喘和几种人类免疫和炎症性疾病。该计划将帮助候选人在学术环境中培训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异性药物。

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.