Cellular and Genetic Determinants that Establish and Diversify Proportion in the Vertebral Skeleton

确定椎骨比例并使其多样化的细胞和遗传决定因素

• 批准号: 10314606
• 负责人: Ceri Weber
• 金额: $ 6.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314606
• 关键词: Area; Automobile Driving; Biological Models; Biology; Bone Growth; Cartilage; Cell Proliferation; Collaborations; DNA; Data; Development; Diagnostic radiologic examination; Dipodidae; Elements; Embryo; Equilibrium; Evolution; Gene Expression; Genetic Determinism; Genetic Processes; Geometry; Goals; Growth; Head; Hindlimb; Histology; House mice; Human; Hypertrophy; Image; Immunohistochemistry; Individual; Knockout Mice; Laboratories; Length; Limb structure; Literature; Mammals; Measures; Methods; Modeling; Molecular; Molecular Genetics; Morphology; Mus; NPR2 gene; Natriuretic Peptides; Outcome; Pathway interactions; Peptide Signal Sequences; Phenotype; Physiologic Ossification; Posture; Process; Research; Rodent; Role; Skeleton; Spinal Cord; Tail; Testing; Variant; Vertebral column; Vertebrates; bone; insight; interest; microCT; skeletal; sound; spine bone structure; transcriptome sequencing; vertebra body

Project Summary The vertebral skeleton is a defining feature of vertebrates, yet little is known about how it grows and evolves. To investigate the molecular genetic processes driving vertebral growth and proportion, we can look to the tail with its vertebrae of simple geometry and extreme size differences between species. Although humans do not have tails, many mammals use their tails to climb, balance, and communicate and have therefore evolved tails of diverse lengths made up of different numbers of vertebrae with a range of sizes. The tail is therefore highly evolvable and likely represents mechanisms of modular growth control used throughout the axial skeleton. An example of tail diversity in closely related rodents is a comparison of the mouse (Mus musculus) and the bipedal lesser Egyptian jerboa (Jaculus jaculus), which diverged from a common ancestor about 50 million years ago. In addition to its more obviously exaggerated hindlimbs, the jerboa has evolved multiple changes to the vertebral skeleton to support its upright posture, including elongation of individual vertebral elements. The objective of this application is to define the temporal and cellular parameters of vertebral growth in mice and jerboas, then use candidate and unbiased approaches to investigate the molecular mechanisms that underlie vertebral growth rate differences. We hypothesize that local changes in gene expression and control the ability of one bone to grow more or less than another. This hypothesis will be tested in the pursuit of three specific aims: 1) Define the temporal and cellular parameters of vertebral growth that establishes and varies proportion, 2) Reveal the role of natriuretic peptide signaling to drive vertebral growth and differential elongation and, 3) Investigate gene expression differences associated with disproportionate vertebral growth. These aims will be pursed using methods that are established in my laboratory or by collaboration, including: microCT and X-ray imaging and histology, mouse knockout lines, and RNA sequencing. The proposed research takes advantage of sound experimental approaches to understand naturally occurring vertebral variation and phenotypes that are different from those observed in traditional model systems,The significance of these studies lies in an opportunity to open a relatively unexplored area of skeletal biology that will contribute to our understanding of body proportion development and evolution.

项目摘要 椎骨骨骼是脊椎动物的一个定义特征，但对其生长的生长和 进化。为了研究驱动椎骨生长和比例的分子遗传过程，我们可以研究 尾部及其简单几何形状和物种之间极端差异的椎骨。虽然人类 没有尾巴，许多哺乳动物都使用尾巴来攀登，平衡和交流，因此已经进化 多个长度的尾巴由不同数量的椎骨组成，尺寸范围很大。因此尾巴是 高度可转化的，可能代表了整个轴向骨骼中使用的模块化生长控制的机制。 密切相关啮齿动物中尾巴多样性的一个例子是对小鼠（mus musculus）和 两足小埃及埃及耶博亚（jaculus jaculus），与普通祖先分歧约5000万 几年前。除了更明显夸张的后肢外，Jerboa还将多次变化发展为 椎骨骨骼支持其直立的姿势，包括单个椎体元素的伸长。这 该应用的目的是定义小鼠椎骨生长的时间和细胞参数 和Jerboas，然后使用候选和公正的方法来研究分子机制 椎骨生长率差异基础。我们假设基因表达和控制的局部变化 一个骨头比另一骨多或多或少地生长的能力。该假设将在追求三个 具体目的：1）定义建立和不同的椎骨生长的时间和细胞参数 比例，2）揭示纳地尿肽信号传导在驱动椎骨生长和差异伸长的作用 3）研究与椎骨生长不成比例的基因表达差异。这些目标 将使用我的实验室或协作中建立的方法来获取，包括：Microct和 X射线成像和组织学，小鼠敲除线和RNA测序。拟议的研究需要 声音实验方法的优势以理解天然发生的椎骨变化和 与传统模型系统中观察到的表型不同的表型，这些研究的重要性 有机会打开一个相对未开发的骨骼生物学领域，这将为我们的 了解身体比例的发展和进化。