NORA Manufacturing Sector Strategic Goals
9270075 - Musculoskeletal Disorders and Innate Immune SystemStart Date: 10/1/2003
End Date: 9/30/2010
Principal Investigator (PI)Name: Petia Simeonova
Funded By: NIOSH
Primary Goal Addressed3.0
Secondary Goal Addressed
Attributed to Manufacturing
Work-related musculoskeletal disorders (MSDs) represent a variety of disorders which are associated with chronic or acute inflammatory responses involved in both tissue degeneration and regeneration. Our current effort is directed to develop a novel approach to improve healing and return to function after severe traumatic muscle injury. The US Army Institute of Surgical Research expressed a high interest and support of this work. The project will help NIOSH to meet its strategic goal on construction and manufacturing sectors as well as musculoskeletal disorders cross sector to reduce the incidence and severity of work-related musculoskeletal disorders among workers in the U.S. Identifying specific molecular steps involved in regulation of tissue injury and repair will provide a basis for successful diagnosis, treatment, and prevention of musculoskeletal diseases resulting in substantial cost savings and improved health for thousands of workers.
Muscle injuries occur through a variety of mechanisms, including direct trauma, (laceration; contusions; strains) and indirect causes (ischemia; neurological dysfunction). The major events are: membrane destruction, influx of calcium, activation of the intrinsic proteases and the innate immune system. The healing process is a delicate balance between muscle regeneration and fibrogenesis. The complete recovery of muscle tissue and function are compromised by the scar formation with tendency for muscle injury to recur. The manipulation of the innate immune system and specifically pharmacological manipulation of macrophage receptors to affect the pro-myogenic and pro-fibrotic actions of cytokines, chemokines, and growth factors is a highly promising approach for improving of healing and function of injured muscle.
We propose to accomplish the following five tasks:
Task #1: Focusing on pro-fibrotic and pro-myogenic mediators, determine using DNA microarray technology the gene expression profiles for two models of traumatic muscle injury, one in which regeneration of the muscle is complete and one in which regeneration is impaired.
Task #1a: For the two models, determine the level of gene expression for all genes on the cytokine-, growth factor-, and Toll-like receptor-targeted DNA microarrays.
Task #1b: Compare the gene expression profiles for the two models of injury and identify genes that are differentially expressed between the two models.
Task #1c: From the differentially-expressed genes, identify candidate genes for categorization as pro-fibrotic or pro-myogenic mediators.
Task #2: Validate the findings of Task #1. For the candidate "pro-fibrotic and pro-myogenic mediator" genes determined in Task #1
Task #2a: Determine for the two models of injury the levels of gene and protein expression for each candidate gene using quantitative RT-PCR and immunoblotting techniques, respectively.
Task #2b: For each of the previously unstudied candidate genes, determine the cellular localization of its gene product. Determine if the localization is consistent with the gene's known or proposed cellular function.
Task #3: Using macrophage cell cultures, identify immunotherapies (i.e., macrophage modulators) targeting Toll-like receptors that enhance the expression and secretion of mediators which could stimulate muscle regeneration. These assessments will make use of the panel of differentially-expressed pro-fibrotic and pro-myogenic genes determined from Tasks #1 and 2.
Task #4: For immunotherapies found to be promising in Task #3, determine if local application of these immunotherapies to traumatically-injured muscle normalizes or enhances the relative expression of pro-myogenic to pro-fibrotic genes
Task #4a: For the model of traumatic muscle injury in which regeneration is impaired, determine if after immunotherapy application the relative expression of pro-myogenic to pro-fibrotic genes becomes like that for the model of muscle injury in which regeneration is complete.
Task #4b: For the model of traumatic muscle injury in which regeneration is complete, determine if after immunotherapy application the relative expression of pro-myogenic to pro-fibrotic genes is shifted towards one favoring an enhanced or accelerated myogenesis.
Task #5: For the three immunotherapies found to be most effective in Task #4, determine if local application of these immunotherapies to traumatically-injured muscle results in an accelerated, complete recovery as assessed by restoration of morphology and function.
• To identify series of genes which are related to skeletal muscle injury/repair mechanisms.
• To evaluate whether modulation of selected inflammatory proteins and mechanisms alters the repair process in injured muscle.
• To evaluate the role of inflammation in occupational-related musculoskeletal injuries and to provide scientific basis for optimal identification and treatment of these disorders.
• To define the macrophage-secreted mediators which can regulate the balance between regeneration and scarring of injured muscle tissue
• To identify immunotherapies which have a potential to induce and accelerate regeneration of injured muscle. The immunotherapeutic application for enhancing restorative injury repair might be a novel approach with considerable potential impact.
• Multiple peer review publications.
• Presentations at national and international scientific meetings.
• Citations of our findings in scientific publications and documents.
More than 600,000 cases of work-related muscle injury are reported annually in the U.S. with an estimated economic impact of $50 billion. Particularly, construction and mining workers are exposed to physical hazards leading to an increased risk of MSDs. For example, work-related MSDs made up 52,303 (24%) of the 193,765 nonfatal injuries and illnesses in construction in 1999. Understanding the mechanisms of skeletal muscle injury and recovery at a molecular level will help in the identification, treatment and prediction of occupational diseases resulting in substantial cost savings and improved health for thousands of working Americans.
Facilitation of skeletal muscle regeneration and return to function are of major importance to both civilian and military workers with traumatic muscle injuries. Our preliminary project demonstrated a role of innate immune system in skeletal muscle injury and recovery. Based on these findings our current effort is directed to develop a novel approach to improve healing and return to function after severe traumatic muscle injury. Although it is known that immunotherapies can stimulate macrophage functions and have become an attractive approach for enhancing immune responses to infectious diseases, their role in controlling the tissue healing process has not been explored. We hypothesize that the repair of traumatically-injured muscle depends on an optimal local interaction between macrophages and muscle precursor cells, one which is mediated by macrophage-derived cytokines, chemokines, and growth factors. The manipulation of the innate immune system and its effect on healing and function of injured muscle will be evaluated in well established mouse models.
Focusing on pro-fibrotic and pro-myogenic mediators, we will: 1) determine and compare the gene expression profiles for two mouse models of traumatic muscle injury, one in which regeneration is complete and one in which regeneration is incomplete. Distinctly-different profiles will be determined for conditions favoring complete muscle regeneration versus conditions favoring fibrosis and only partial muscle regeneration. 2) Determine the main Toll-like receptors that are found in muscle tissue following injury. 3) Using macrophage cell cultures, we will identify immunotherapies that enhance the expression and secretion of mediators which could stimulate muscle regeneration. 4) For the immunotherapies found promising in macrophage cell cultures, determine if local application of these immunotherapies to injured muscle normalizes or enhances the relative expression of pro-myogenic to pro-fibrotic genes, i.e., to one favoring complete and/or accelerated regeneration with a reduction in scarring. 5) For the three immunotherapies found to be most effective in aim #4, determine if local application of these immunotherapies to injured muscle results in a more rapid and complete restoration of muscle morphology (i.e., muscle and myofiber size) and function (i.e., in vivo muscle strength and shortening velocity).
In general, the project will provide beneficial findings which can be used to improve rehabilitation and quality of life of injured workers and soldiers. The US Army Institute of Surgical Research expressed a high interest and support of this work.
Construction sector (50%)
STRATEGIC GOAL 7.0 – 09PPCONSG7 Reduce the incidence and severity of work-related musculoskeletal disorders among construction workers in the U.S.
Manufacturing sector (50%)
STRATEGIC GOAL 3.0 – 09PPMNFSG3 Reduce the number of musculoskeletal disorders among manufacturing sector workers.
Musculoskeletal Disorders Cross Sector (100%)
Strategic Goal 2 (09PPMSDSG2) (Causes): Definitive understanding of the multi-factorial relationships among exposures, risk factors, and MSDs
IG2.2 (09PPMSDIG2.2) (Physiological): Understanding of the continuum of biological mechanisms associated with the development of and recovery from MSDs
IG2.4 (09PPMSDIG2.4) (Individual): Understanding of host factors that influence development of and recovery from MSDs
This study is seen by the Army as being very important because traumatic limb injuries occur on a daily basis on the battle fields.
Justification: Musculoskeletal disorders are highly related to construction work and many other industries. We are evaluating factors and conditions which can be used to understand the development, prevention, and treatment of musculoskeletal disorders. The project will have a direct application in development of new strategies for recovery from severe traumatic limb injuries which are serious problem for the Army.
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