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

• 批准号: 9274036
• 负责人: LUCAS R SMITH
• 金额: $ 9.29万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274036
• 关键词: Acute; Address; Adverse effects; Advisory Committees; Affect; Alpha Cell; Architecture; Award; Basement membrane; Biochemical; Biology; Biomedical Engineering; Cell Differentiation process; Cell Maturation; Cell Proliferation; 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; skills; stem cell biology; success; symposium; therapeutic target; tissue culture; training opportunity

 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人员，在肌肉生理学领域做出实质性贡献，并将其转化为肌肉疾病的临床相关疗法。这一奖励机制将有助于提供实现目标的能力，为我过渡到独立提供必要的持续培训。我在生物工程和肌肉生理学研究的背景提供了一个突出的问题，肌肉纤维化如何导致受损的功能和再生的重点。为了充分解决这个问题，我已经获得了一位杰出的导师的支持，他是细胞对细胞外基质特性的反应的生物工程师，Discher博士。他的指导将由我的共同导师巴顿博士补充，他将继续提供肌肉生理学方面的特殊指导。Soslowsky博士将提供进一步的指导，他将在我的咨询委员会中任职。该委员会将定期开会，以确保项目里程碑的适当进展，必要时评估替代策略，并监督我向独立的过渡。我还将与合作者合作;岩本博士在严重肌肉损伤模型方面具有专业知识，山内溥博士是胶原蛋白转录后修饰的权威。宾夕法尼亚大学的环境非常适合进行拟议的研究，在很大程度上来自宾夕法尼亚肌肉研究所，该研究所在对肌肉的各个方面感兴趣的教师队伍中提供各种培训机会。在该奖项的指导阶段的教学将扩大我的研究范围，并降低在我的职业生涯中尝试新方法的障碍。宾大还为博士后获得教职提供支持服务，我将通过生物医学博士后项目办公室充分利用这些服务。宾夕法尼亚大学杰出的机构环境将得到佛罗里达大学与共同导师巴顿博士和北卡罗来纳州大学与合作者山内博士的培训的补充。这项研究的结果将通过同行评审的出版物和在具有相关利益的国家会议上的介绍与公众分享。在我领导下 项目，参与的支持系统将确保成功实现我的目标的每一个机会。 纤维化是细胞外基质（ECM）组分在组织内的病理性积累，导致结构破坏和功能丧失。骨骼肌在包括肌营养不良和严重肌肉损伤在内的许多疾病中发生纤维化。在骨骼肌内，ECM不仅提供细胞支架，而且还具有传递肌纤维产生的力的额外作用，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，然而胶原的量并不决定损伤的程度，这表明胶原组织的其他参数起着重要作用。由于目前还没有批准的治疗骨骼肌纤维化的药物，我的长期目标是创建治疗靶点和框架，用于测试骨骼肌中的抗纤维化药物。我的中心假设是，胶原组织的参数在纤维化中被破坏，包括交联，排列和包装，并且这种破坏损害肌肉功能和再生。我还将测试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。本研究的目的是确定骨骼肌纤维化胶原组织的新参数，并对该组织进行调控，以探索骨骼肌纤维化的再生机制，为治疗提供新的靶点。在K99部分的赠款，我将追求目标1：确定胶原组织是如何改变肌肉纤维化。我们将确定ECM组织、胶原交联、胶原排列和胶原包装的参数如何与主动和被动肌肉功能相关。我们将检验骨骼肌纤维化中胶原组织而不仅仅是胶原数量改变的假设。在该奖项的指导阶段，我将获得基质工程和干细胞生物学的新技能，以便在R 00阶段追求目标2：确定胶原组织如何影响卫星细胞再生。我推测卫星细胞在胶原组织破坏的基质上的成熟将受到损害。最后，在K99期间，我将优化在R 00阶段测试的治疗方案，以实现目标3：确定抑制胶原交联是否会改善肌肉纤维化的功能和再生。我将检验β-氨基丙腈（一种交联抑制剂）作为抗纤维化治疗有效的假设。这些研究将利用我以前在肌肉生理学方面的研究专长，但也需要在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。在这个项目的结论，我将能够定义的关键特点，胶原组织在纤维化的骨骼， 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，靶向胶原组织作为一种潜在的治疗骨骼肌纤维化。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，这是由该奖项提供的指导培训所实现的。