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

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.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Midcareer Investigator Award in Biomedical and Behavioral Research (K26)
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National Center for Research Resources Initial Review Group (RIRG)
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Mirochnitchenko, Oleg
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Children's Research Institute
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Echigoya, Yusuke; Lim, Kenji Rowel Q; Trieu, Nhu et al. (2017) Quantitative Antisense Screening and Optimization for Exon 51 Skipping in Duchenne Muscular Dystrophy. Mol Ther 25:2561-2572
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Vila, Maria Candida; Klimek, Margaret Benny; Novak, James S et al. (2015) Elusive sources of variability of dystrophin rescue by exon skipping. Skelet Muscle 5:44
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