Regulation of organogenesis through regional variations in tissue mechanics

通过组织力学的区域差异调节器官发生

• 批准号: 10330989
• 负责人: Otger Campas
• 金额: $ 46.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330989
• 关键词: Address; Affect; Anisotropy; Biochemical; Biological Models; Biology; Biomedical Engineering; Bypass; Cell Density; Cell Differentiation process; Cell Proliferation; Cell Size; Cells; Data; Dental Enamel; Dental caries; Development; Drug or chemical Tissue Distribution; E-Cadherin; Epithelial; Event; Future; Generations; Genes; Goals; Image; In Situ; In Vitro; Knowledge; Learning; Link; Measurement; Measures; Mechanical Stress; Mechanics; Mediator of activation protein; Mesenchyme; Methods; Modeling; Molecular; Monitor; Morphogenesis; Mutation; Myosin Type II; Nuclear; Nuclear Protein; Oils; Organ; Organogenesis; Pattern; Phenotype; Play; Process; Proteins; Public Health; Publishing; Regulation; Research; Role; Signal Pathway; Signal Transduction; Spatial Distribution; Stress; Techniques; Testing; Time; Tissues; Tooth Germ; Tooth Loss; Tooth structure; Transducers; Variant; alpha catenin; cell behavior; cell type; craniofacial; design; driving force; embryo tissue; experimental study; genetic approach; in vivo; interest; mechanical force; mechanical signal; mouse genetics; mutant; new technology; non-muscle myosin; novel; protein distribution; public health relevance; regional difference; spatiotemporal; Address; Affect; Anisotropy; Biochemical; Biological Models; Biology; Biomedical Engineering; Bypass; Cell Density; Cell Differentiation process; Cell Proliferation; Cell Size; Cells; Data; Dental Enamel; Dental caries; Development; Drug or chemical Tissue Distribution; E-Cadherin; Epithelial; Event; Future; Generations; Genes; Goals; Image; In Situ; In Vitro; Knowledge; Learning; Link; Measurement; Measures; Mechanical Stress; Mechanics; Mediator of activation protein; Mesenchyme; Methods; Modeling; Molecular; Monitor; Morphogenesis; Mutation; Myosin Type II; Nuclear; Nuclear Protein; Oils; Organ; Organogenesis; Pattern; Phenotype; Play; Process; Proteins; Public Health; Publishing; Regulation; Research; Role; Signal Pathway; Signal Transduction; Spatial Distribution; Stress; Techniques; Testing; Time; Tissues; Tooth Germ; Tooth Loss; Tooth structure; Transducers; Variant; alpha catenin; cell behavior; cell type; craniofacial; design; driving force; embryo tissue; experimental study; genetic approach; in vivo; interest; mechanical force; mechanical signal; mouse genetics; mutant; new technology; non-muscle myosin; novel; protein distribution; public health relevance; regional difference; spatiotemporal

ABSTRACT The long-term goal of the proposed research is to understand the mechanisms that regulate organogenesis. The overall objective of the proposal is to use our novel in vivo force transducers, which allow quantitative measurements of mechanical stresses within living embryonic tissues, to unveil the role of mechanical signals in the specification of signaling centers and cell types during organ morphogenesis, using the tooth as a model system. The central hypothesis is that the endogenous regional variations in compressive and tensile stresses in the tissue control the distribution of nuclear YAP localization in the developing tooth, thereby regulating specification of key signaling centers. The following Specific Aims will employ a combination of novel technologies designed to measure mechanical stresses in vivo and in situ with sophisticated mouse genetic strategies. Aim 1 will characterize regional differences in endogenous compressive and tensile stresses during tooth development. These experiments will constitute the first ever measurement of regional differences in compressive and tensile stresses during the formation of any vertebrate organ. These regional changes in mechanics will be related to spatial variations in YAP nuclear localization in the tissue and the establishment of signaling centers. Aim 2 will determine the molecular control of signaling center formation by tensile and compressive stresses in the developing tooth in vivo. In order to link the in vivo stress measurements to the molecules controlling the mechanical phenotype, we will first image the spatiotemporal distribution of proteins involved in force generation. Moreover, we will genetically delete the genes encoding these proteins and determine how mutations in these genes affect YAP localization and the ability to generate compressive and tensile stresses in the tissue. Aim 3 will reveal the role of mechanical stresses in the regulation of nuclear vs. cytoplasmic YAP localization in vivo. These experiments will directly test our hypothesis that regional differences in compressive and tensile stresses in the tissue control the tissue distribution of nuclear YAP localization. Together, these studies will provide a leap forward in our knowledge of how tooth development is regulated by a novel signal, mechanical stress. Such information about the fundamental biology of tooth development will in turn enhance future efforts in applications such as tooth bioengineering.

抽象的 拟议研究的长期目标是了解调节器官发生的机制。 该提案的总体目的是使用我们的小说中的体内力传感器，这允许定量 测量活的胚胎组织中的机械应力，以揭示机械信号的作用 在器官形态发生过程中信号传导中心和细胞类型的规范中，使用牙齿作为模型 系统。中心假设是压缩和拉伸的内源性区域变化 组织中的应力控制发育中牙齿中核YAP定位的分布，从而 调节关键信号中心的规范。以下具体目标将采用 新型技术旨在用复杂的小鼠在体内和原位测量机械应力 遗传策略。 AIM 1将表征内源性压缩和拉伸的区域差异 牙齿发育过程中的压力。这些实验将构成有史以来第一个区域的测量 在任何脊椎动物器官形成过程中，压缩应力和拉伸应力的差异。这些区域 力学的变化将与组织和组织中YAP核定位的空间变化有关 建立信号中心。 AIM 2将确定信号传导中心的分子控制 在体内发育中的牙齿中通过拉伸和压缩应力形成。为了链接体内 对控制机械表型的分子的应力测量，我们将首先对 涉及力产生的蛋白质的时空分布。而且，我们将遗传删除 编码这些蛋白质的基因，并确定这些基因突变如何影响YAP定位和 能够在组织中产生压缩应力和拉伸应力。 AIM 3将揭示机械的作用 体内核和细胞质YAP定位调节的应力。这些实验会 直接检验我们的假设，即组织控制中压缩应力和拉伸应力的区域差异 核YAP定位的组织分布。这些研究一起将在我们的 了解牙齿发育如何受到新信号的调节，机械应力。这样的信息 牙齿发育的基本生物学反过 生物工程。