Model Systems of Mammalian Regeneration

哺乳动物再生模型系统

• 批准号: 9750191
• 负责人: Chelsey Savannah Simmons
• 金额: $ 36.9万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750191
• 关键词: Acomys; Acute Disease; Adult; African; Animal Model; Award; Biological Models; Burn injury; Cell physiology; Cells; Cessation of life; Chronic Disease; Cicatrix; Communities; Complement; Educational process of instructing; Engineering; Feedback; Fibroblasts; Fibrosis; Future; Goals; Histologic; Human; Immunocompromised Host; In Vitro; Injury; Lead; Macrophage Activation; Mechanics; Mentors; Modeling; Mus; Myocardial Infarction; Natural regeneration; Pathway interactions; Process; Property; Research; Research Personnel; Services; Site; Spinal cord injury; Stromal Cells; Thick; Tissues; Translations; Transplantation; Trauma; Vision; Work; cell behavior; improved; induced pluripotent stem cell; interest; mechanical properties; muscle necrosis; novel; programs; recruit; rho GTP-Binding Proteins

PROJECT SUMMARY/ABSTRACT Since I launched my independent research program in 2013, we have focused at the intersection of mechanics and biomedicine. Specifically, I am interested in the mechanobiological feedback loop between cells and matrix mechanics wherein mechanical properties of matrix drive cell behavior which in turn modify tissue-level matrix properties. I have long been interested in the effects of the mechanical microenvironment on cell function, but the focus of my independent work has shifted to stromal cells and fibrosis. Fibrosis accompanies many acute and chronic diseases and is the cause of >40% of deaths in the U.S. Fibrotic processes often increase the effective stiffness of tissue in addition to traditional histological metrics. My vision for is to build model systems of mammalian regeneration, to identify mechanisms of cell contractility, and to target downstream effectors that control fibroproliferative cell function. To accomplish these goals, I am leveraging a novel model of mammalian regeneration, the African Spiny Mouse. The African Spiny Mouse (Acomys) can regenerate normal matrix after injury, with minimal scar tissue after many types of trauma, including full-thickness cuts, burns, myocardial infarction, spinal cord injury, and muscle necrosis. Unfortunately, what enables this adult mouse’s with this remarkable ability to regenerate normal matrix is currently poorly understood. The Maximizing Investigators’ Research Award will enable me and my collaborators to determine the mechanisms of normal matrix regeneration in Acomys. My specific five-year goals are to (i) utilize engineered in vitro platforms to identify Rho GTPase pathways that may be altered in Acomys and leverage those mechanisms to minimize fibrosis in normal fibroblasts; (ii) utilize immunocompromised mice that have been transplanted with Acomys cells or tissues to investigate recruitment and activation of macrophages to sites of injury/regeneration; and (iii) create Acomys induced pluripotent stem cells for future use as in vitro and chimeric animal model systems. To complement these research objectives, I will continue teaching, mentoring, professional service, and community engagement to promote research and translation at the intersection of engineering and biomedicine.

项目摘要/摘要 自2013年启动独立研究计划以来，我们一直专注于机械师的交集 和生物医学。具体而言，我对细胞和矩阵之间的机械反馈回路感兴趣 矩阵驱动细胞行为的机械特性又改变了组织级矩阵 特性。我长期以来一直对机械微环境对细胞功能的影响感兴趣，但是 我独立工作的重点已转移到基质细胞和纤维化。纤维化涉及许多急性 和慢性疾病，是美国纤维化过程中死亡的40％的原因通常会增加 除传统的组织学指标外，组织的有效刚度。 我的愿景是建立哺乳动物再生的模型系统，以确定细胞收缩的机制， 并靶向控制纤维增生细胞功能的下游效应。为了实现这些目标，我是 利用一种新型的哺乳动物再生模型，非洲的棘小鼠。非洲棘小鼠 （ACOMYS）受伤后可以再生正常基质，在多种类型的创伤之后，疤痕组织最小， 包括全厚度切割，烧伤，心肌梗塞，脊髓损伤和肌肉坏死。 不幸的是，可以使这只成年鼠标具有这种非凡的重生正常矩阵的能力是 目前了解不足。最大化调查人员的研究奖将使我和我的 合作者确定ACCOMYS中正常基质再生的机制。 我的特定五年目标是（i）利用体外平台进行工程的识别Rho GTPase 可能会改变Accomys并利用这些机制以最大程度地减少纤维化的途径 正常成纤维细胞； （ii）利用已被Accomys移植的免疫功能低下的小鼠 细胞或时间安排研究巨噬细胞的募集和激活 伤害/再生； （iii）创建Accomys诱导多能干细胞，以供将来用作体外用途 和嵌合动物模型系统。为了完成这些研究目标，我将继续 教学，心理，专业服务和社区参与，以促进研究和 工程和生物医学交集的翻译。