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: 10684025
• 负责人: Ceri Weber
• 金额: $ 7.18万
• 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/10684025
• 关键词: Area; Automobile Driving; Biological Models; Biology; Bone Growth; Cartilage; Cell Proliferation; Collaborations; Communication; DNA; Data; Development; 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; X-Ray Medical Imaging; 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.

项目概要 椎骨是脊椎动物的一个决定性特征，但人们对其如何生长和发育知之甚少。 进化。为了研究驱动椎骨生长和比例的分子遗传过程，我们可以看看 尾部的椎骨几何结构简单，物种之间的尺寸差异极大。虽然人类 没有尾巴，许多哺乳动物用尾巴来攀爬、平衡和交流，因此进化了 不同长度的尾巴由不同数量、不同尺寸的椎骨组成。因此尾巴是 高度进化，可能代表整个轴向骨架使用的模块化生长控制机制。 密切相关的啮齿动物尾巴多样性的一个例子是小鼠（Mus musculus）和 双足小埃及跳鼠 (Jaculus jaculus)，与大约 5000 万的共同祖先分化 几年前。除了更加明显夸张的后肢之外，跳鼠还进化出了多重变化 椎骨支撑其直立姿势，包括各个椎骨的伸长。这 该应用的目的是定义小鼠椎骨生长的时间和细胞参数 和跳鼠，然后使用候选和无偏见的方法来研究分子机制 造成椎骨生长速度差异的原因。我们假设基因表达和控制的局部变化 一根骨头比另一根骨头生长得更多或更少的能力。该假设将在三个方面进行检验 具体目标： 1) 定义椎体生长的时间和细胞参数，这些参数建立和变化 比例，2）揭示利尿钠肽信号传导在驱动椎体生长和差异伸长中的作用 3) 研究与不成比例的椎骨生长相关的基因表达差异。这些目标 将使用我的实验室或合作建立的方法进行研究，包括：microCT 和 X 射线成像和组织学、小鼠基因敲除系和 RNA 测序。拟议的研究需要 利用健全的实验方法来了解自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，这些研究的意义 在于有机会打开骨骼生物学相对未开发的领域，这将有助于我们 了解身体比例的发展和进化。