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The role of collagen organization in determination of fibrotic muscle function and regeneration

胶原组织在纤维化肌肉功能和再生测定中的作用

基本信息

批准号：
9788030
负责人：
LUCAS R SMITH
金额：
$ 24.8万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788030
关键词：
Acute Address Advisory Committees Affect Architecture Award Basement membrane Biochemical Biology Biomedical Engineering Cell Differentiation process Cell Maturation Cell Proliferation Cells Cessation of life Cicatrix Collagen Complement Deposition Engineering Ensure Environment Extracellular Matrix Extracellular Structure Faculty Fibrillar Collagen Fibrosis Florida Foundations Genetic Transcription Goals Grant Impairment In Vitro Injury Institutes Knowledge LOX gene Leadership Maintenance Measures Mentors Mentorship Modeling Modification Monitor Muscle Muscle Cells Muscle Fibers Muscle function Muscular Atrophy Muscular Dystrophies Myopathy Natural regeneration Nature North Carolina Pathologic Peer Review Pennsylvania Phase Play Polarization Microscopy Positioning Attribute Postdoctoral Fellow Prevention Production Property Protein-Lysine 6-Oxidase Publications Research Research Personnel Role Scientist Services Skeletal Muscle Solubility Structure Support System Techniques Testing Therapeutic Tissues Training Training Programs Translating Treatment Protocols Universities Weight-Bearing state Work authority base beta Aminopropionitrile career cell motility clinically relevant crosslink density effective therapy experience improved improved functioning in vivo inhibitor/antagonist interest loss of function migration mouse model muscle physiology muscle regeneration novel strategies novel therapeutics premature programs public health relevance regenerative repaired response satellite cell scaffold side effect skills stem cell biology success symposium therapeutic target tissue culture training opportunity

项目摘要

DESCRIPTION (provided by applicant): My long term career goal is to become an independent academic researcher, making substantial contributions in the field of muscle physiology that are translated into clinically relevant therapies for those with muscle diseases. This award mechanism would be instrumental in the providing the ability to reach goal by providing the continued training necessary for me to transition to independence. My background in bioengineering and muscle physiology research has provided a focus on outstanding question of how muscle fibrosis leads to impaired function and regeneration. To adequately address this question I have garnered the support of an outstanding mentor in bioengineering of cellular responses to extracellular matrix properties, Dr. Discher. His mentorship will be supplemented by that of my co-mentor Dr. Barton, who will continue to provide exceptional mentorship in muscle physiology. Further guidance will be provided by Dr. Soslowsky, who will serve on my advisory committee. This committee will meet regularly to ensure adequate progress toward project milestones, assess alternative strategies when necessary, and monitor my transition to becoming independent. I will also work with collaborators; Dr. Iwamoto who has expertise in severe muscle injury models and Dr. Yamauchi who is an authority on collagen post-transcriptional modifications. The environment at Penn is ideal for conducting the proposed research, in large part from the Pennsylvania Muscle Institute which provides various training opportunities among a cadre of engaged faculty interested in a variety of aspects of muscle. Didactics during the mentored phase of the award will broaden the scope of my research and lower barriers to attempting new approaches in my career. Penn also provides support services for postdocs acquiring faculty positions that I will take full advantage of through the Biomedical Postdoctoral Program Office. The outstanding institutional environment at the University of Pennsylvania will be supplemented by training at the University of Florida with co-mentor Dr. Barton and at the University of North Carolina with collaborator Dr. Yamauchi. The results of this research proposed will be shared with the public through peer reviewed publications and presentations at national conferences with relevant interests. While I will take leadership of this project, the support system engaged will ensure every opportunity for success in acquiring my goals. Fibrosis is the pathologic accumulation of extracellular matrix (ECM) components within a tissue leading to disrupted architecture and loss of function. Skeletal muscle undergoes fibrosis in response to many conditions including muscular dystrophies and severe muscle injury. Within skeletal muscle the ECM not only provides a cell scaffold, but has the additional role of transmitting forces produced by muscle fibers, making ECM critical to muscle function. My past research in skeletal muscle has demonstrated how fibrosis compromises muscle in many conditions, but also highlighted how little is known about the structure of fibrotic material. Fibrotic tissue is primarily made of up fibrillar collagen, however the amount of collagen does not determine the degree of impairment, suggesting further parameters of collagen organization play an important role. As there is currently no approved therapeutic to treat skeletal muscle fibrosis, my long term goal is to create therapeutic targets and a frame work for testing anti-fibrotics in skeletal muscle. My central hypothesis is that parameters of collagen organization are disrupted in fibrosis, including cross-linking, alignment, and packing, and that this disruptio impairs muscle function and regeneration. I will also test the hypothesis that inhibiting cross-linking in fibrotic muscle will reduce fibrosis, improve function, and regeneration. My objective i to define new parameters of collagen organization of skeletal muscle fibrosis and manipulate that organization in order to probe muscle regeneration and provide therapeutic targets. During the K99 portion of the grant I will pursue Aim 1: Determine how collagen organization is altered in muscle fibrosis. We will determine how parameters of the ECM organization, collagen cross-linking, collagen alignment, and collagen packing relate to active and passive muscle function. We will test the hypothesis that collagen organization, not just collagen quantity, is altered in skeletal muscle fibrosis. During the mentored phase of the award I will obtain new skills in matrix engineering and stem cell biology in order to pursue in the R00 phase Aim 2: Determine how collagen organization effects satellite cell regeneration. I hypothesize satellite cell maturation on substrates with disrupted collagen organization will be impaired. Finally during the K99 I will optimize a treatment regimen to be tested during the R00 phase leading to Aim 3: Determine if inhibiting collagen cross-linking leads to improved function and regeneration of muscle fibrosis. I will test the hypothesis that β-aminopropionitrile, a cross-linking inhibitor, an be effective as an anti-fibrotic treatment. These studies will take advantage of my previous research expertise in muscle physiology, but also require training in the analysis of muscle collagen and the engineering of matrix substrates in tissue culture. At the conclusion of this project, I will be able to define the key features of collagen organization in fibrosis of skeletal muscle and their relation to muscle function and satellite cell regeneration. I will also provide evidence for targeting collagen organization as a potential therapy to treat skeletal muscle fibrosis. This research will lay the foundation for my career as an independent scientist made possible by the mentored training provided by this award.