Quantitative dissection of the events that encode bone size and shape during regeneration

再生过程中编码骨骼大小和形状的事件的定量剖析

• 批准号: 10386597
• 负责人: Ashley Rich Baker
• 金额: $ 6.72万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386597
• 关键词: Address; Amputation; Biological Assay; Biological Process; Biosensor; Body Size; Bone Matrix; Bone Regeneration; Cell Differentiation process; Cell Proliferation; Cells; Computing Methodologies; Data; Development; Digit structure; Dissection; Environment; Event; Exhibits; Extracellular Signal Regulated Kinases; Feedback; Genetic; Goals; Growth; Growth Factor; Hour; Human; Hypertrophy; Image; Individual; Injury; Lateral; Length; Ligands; Mammals; Maps; Medial; Mentorship; Mesenchymal; Modeling; Molecular; Natural regeneration; Nature; Osteoblasts; Pathway interactions; Pattern; Pharmacology; Process; Proliferating; Research; Resolution; Role; Shapes; Signal Pathway; Signal Transduction; Structure; System; Testing; Time; Tissues; Training; Traumatic Amputation; Traumatic injury; Travel; Universities; Work; Writing; Zebrafish; appendage; base; bone; bone fracture repair; desensitization; experimental study; imaging modality; imaging platform; injured; insight; migration; novel; optogenetics; osteoblast differentiation; regenerative; regenerative biology; spatiotemporal; therapeutic target; tissue regeneration

ABSTRACT Mammals possess a limited compacity to regenerate appendages following traumatic injury and amputation, including regenerating digit tips and healing of bone fractures. In contrast, zebrafish can regenerate entire appendages following amputation. As in development, regenerated appendages are scaled appropriately to body size. Extensive genetic and pharmacological experiments have established that canonical signaling pathways, such as Fgf and Wnt, are reactivated following injury to promote the cell proliferation, migration, and differentiation that drives regeneration of appendages. However, how these pathways encode size and shape is unclear. This is due, in part, to the limited number of quantitative and dynamic descriptions of these signaling pathways and their downstream cellular events during regeneration. To address these gaps in the understanding of appendage scaling during regeneration, this proposal aims to develop a quantitative, live imaging platform for zebrafish caudal fin regeneration. Specifically, Aim 1 will determine the role of extracellular signal-regulated kinase (ERK) in encoding cell proliferation and bone size during fin ray regeneration. Aim 2 will define the role of negative feedback during fin regeneration and investigate whether this negative feedback contributes to the robustness of this regeneration event. Collectively, this work will establish a quantitative model for interrogating the cellular basis of size and shape control during regeneration. This work will be conducted at Duke University under the mentorship of Dr. Di Talia and Dr. Poss. This is a highly collaborative training environment that affords expertise in quantitative and regenerative biology. This proposed research will be carried out alongside focused training in quantitative approaches, scientific writing, and mentorship.

抽象的 哺乳动物在遭受创伤和截肢后再生附肢的能力有限， 包括再生指尖和骨折愈合。相比之下，斑马鱼可以再生整个 截肢后的附肢。在开发过程中，再生的附属物会适当缩放 车身尺寸。广泛的遗传和药理学实验已经证实，经典信号传导 Fgf 和 Wnt 等通路在损伤后重新激活，促进细胞增殖、迁移和 驱动附属物再生的分化。然而，这些通路如何编码大小和形状 尚不清楚。部分原因是这些信号的定量和动态描述数量有限 再生过程中的途径及其下游细胞事件。为了解决这些差距 了解再生过程中的附属物缩放，该提案旨在开发定量的、实时的 斑马鱼尾鳍再生成像平台。具体来说，目标 1 将确定细胞外的作用 信号调节激酶（ERK）在鳍条再生过程中编码细胞增殖和骨大小。目标2 将定义负反馈在鳍再生过程中的作用，并研究这种负反馈是否 有助于该再生事件的稳健性。总的来说，这项工作将建立一个定量的 用于询问再生过程中尺寸和形状控制的细胞基础的模型。这项工作将是 在杜克大学 Di Talia 博士和 Poss 博士的指导下进行。这是一个高度协作的 提供定量和再生生物学专业知识的培训环境。这项拟议的研究 将与定量方法、科学写作和指导方面的重点培训一起进行。