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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：
9982777
负责人：
LUCAS R SMITH
金额：
$ 24.43万
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/9982777
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 cell regeneration clinically relevant crosslink density effective therapy engineered stem cells 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 severe injury 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.

描述（由申请人提供）：我的长期职业目标是成为一名独立的学术研究员，在肌肉生理学领域做出重大贡献，并将其转化为针对肌肉疾病患者的临床相关疗法。该奖励机制将有助于通过为我提供过渡到独立所需的持续培训来实现目标的能力。我在生物工程和肌肉生理学研究方面的背景使我重点关注肌肉纤维化如何导致功能和再生受损的突出问题。为了充分解决这个问题，我获得了细胞对细胞外基质特性的反应生物工程方面的杰出导师 Discher 博士的支持。我的搭档巴顿博士将补充他的指导，巴顿博士将继续在肌肉生理学方面提供卓越的指导。索斯洛夫斯基博士将提供进一步的指导，他将担任我的顾问委员会成员。该委员会将定期举行会议，以确保项目里程碑取得足够进展，必要时评估替代策略，并监督我向独立的过渡。我也会和合作者一起工作；岩本博士在严重肌肉损伤模型方面拥有丰富的专业知识，山内博士是胶原蛋白转录后修饰领域的权威。宾夕法尼亚大学的环境非常适合进行拟议的研究，很大程度上来自宾夕法尼亚肌肉研究所，该研究所为对肌肉各个方面感兴趣的敬业教师骨干提供各种培训机会。奖项指导阶段的教学将扩大我的研究范围，并降低我在职业生涯中尝试新方法的障碍。宾夕法尼亚大学还为获得教职的博士后提供支持服务，我将通过生物医学博士后项目办公室充分利用这些服务。宾夕法尼亚大学出色的制度环境将通过在佛罗里达大学与合作导师巴顿博士以及在北卡罗来纳大学与合作者山内博士的培训得到补充。这项研究的结果将通过同行评审的出版物和在有相关兴趣的全国会议上的演讲与公众分享。虽然我将领导这件事项目，所涉及的支持系统将确保我成功实现目标的每一个机会。纤维化是组织内细胞外基质 (ECM) 成分的病理性积累，导致结构破坏和功能丧失。骨骼肌因许多情况而发生纤维化，包括肌营养不良和严重肌肉损伤。在骨骼肌内，ECM 不仅提供细胞支架，还具有传递肌纤维产生的力的附加作用，这使得 ECM 对肌肉功能至关重要。我过去对骨骼肌的研究已经证明了纤维化如何在许多情况下损害肌肉，但也强调了人们对纤维化材料的结构知之甚少。纤维化组织主要由纤维状胶原组成，但胶原蛋白的量并不能决定损伤程度，这表明胶原组织的进一步参数发挥着重要作用。由于目前没有批准的治疗方法来治疗骨骼肌纤维化，我的长期目标是创建治疗目标和测试骨骼肌抗纤维化的框架。我的中心假设是，胶原蛋白组织的参数在纤维化过程中被破坏，包括交联、排列和堆积，并且这种破坏会损害肌肉功能和再生。我还将验证抑制纤维化肌肉中的交联将减少纤维化、改善功能和再生的假设。我的目标是定义骨骼肌纤维化胶原组织的新参数并操纵该组织以探测肌肉再生并提供治疗目标。在拨款的 K99 部分期间，我将追求目标 1：确定胶原蛋白组织在肌肉纤维化中如何改变。我们将确定 ECM 组织、胶原蛋白交联、胶原蛋白排列和胶原蛋白堆积的参数如何与主动和被动肌肉功能相关。我们将检验以下假设：在骨骼肌纤维化中，胶原蛋白组织（而不仅仅是胶原蛋白数量）发生了改变。在该奖项的指导阶段，我将获得基质工程和干细胞生物学方面的新技能，以便在 R00 阶段实现目标 2：确定胶原蛋白组织如何影响卫星细胞再生。我假设卫星细胞在胶原组织破坏的基质上的成熟会受到损害。最后，在 K99 期间，我将优化在 R00 阶段测试的治疗方案，从而实现目标 3：确定抑制胶原蛋白交联是否会改善肌肉纤维化的功能和再生。我将检验以下假设：β-氨基丙腈（一种交联抑制剂）作为抗纤维化治疗有效。这些研究将利用我之前在肌肉生理学方面的研究专业知识，但也需要接受肌肉胶原蛋白分析和组织培养中基质基质工程方面的培训。在这个项目结束时，我将能够定义骨骼纤维化中胶原蛋白组织的关键特征肌肉及其与肌肉功能和卫星细胞再生的关系。我还将提供证据，证明以胶原蛋白组织为治疗骨骼肌纤维化的潜在疗法。这项研究将为我作为一名独立科学家的职业生涯奠定基础，而该奖项提供的指导培训使我成为可能。