Development of a human skeletal muscle cell-based high throughput screen for musc
Department of Health and Human Services
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AbstractDESCRIPTION (provided by applicant): Skeletal muscle wasting is a serious condition prevalent in the aging population (sarcopenia) and in a variety of specific diseases. This condition results in loss of muscle function through impaired muscle regeneration, resulting in an increase in falls and injuries, a loss of independence, and a reduced quality of life. These changes produce a large health care burden estimated in the year 2000 to be 18.5 billion in the aged population. Since the morbidity and mortality rates are directly correlated to the mobility of elderly subjects, new medicines that promote muscle regeneration should lower health care costs through less hospitalization and nursing home care. Muscle regeneration is controlled by the satellite cell,an adult muscle stem cell. When muscle is injured, the satellite cell becomes activated to proliferate and subsequently differentiate to terminally committed myoblasts. The overall objective of this application is to establish a human satellite cell-basedsystem that can support: 1) identification of the signaling pathways and agents that control the proliferation of satellite cells, 2) studies of the alterations that underlie muscle wasting, and 3) drug discovery programs on muscle regeneration. In Aim1 using human muscle biopsy material, we will establish a satellite cell assay in a 384-well format that can determine the capacity of the cells to proliferate, maintain their satellite cell phenotype and allow measurement of the effects of different agents on these properties. This platform will establish a robust screening system that can be used in Phase II work to identify agents that modify the cells' capacity to replicate and differentiate. Efforts in Aim 2 will validate the assay by examining a set of agents with known effects on skeletal muscle. The utility of the assay will be demonstrated by screening small libraries of highly annotated compounds. Importantly, this work will be the first step toward identifying novel mechanisms and molecules that promote muscle regeneration. The screening assay will become part of Zen Bio's contract assay service when it is refined by work in Phase II, allowing pharmaceutical, biotech and academic institutions to profile the actions of compounds and biological agents on human satellite cells. Phase II efforts will also help Zen Bio develop an intellectual property portfolio that covers chemical and target-driven information on muscle regeneration. PUBLIC HEALTH RELEVANCE: Muscle wasting is a major problem in theelderly and in a variety of specific diseases (e.g. chronic obstruction pulmonary disease, cancer related cachexia, end stage renal disease). This application describes the generation of a cell-based assay system using the human satellite cell, an adult stem cell that controls skeletal muscle regeneration. This assay will provide a method for determining the controls that regulate human satellite cell proliferation, examine the cause of the poor muscle regeneration seen in various states such as elderly subjects and the disease states mentioned above, and facilitate the identification of new drugs that can reverse the age and disease-related decline in muscle mass and function.
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