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: 10478892
• 负责人: Ceri Weber
• 金额: $ 6.76万
• 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/10478892
• 关键词: Area; Automobile Driving; Biological Models; Biology; Bone Growth; Cartilage; Cell Proliferation; Collaborations; 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.

项目摘要 脊椎骨骼是脊椎动物的一个决定性特征，但人们对它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，我们可以研究 尾椎的几何形状简单，不同物种之间的大小差异极大。尽管人类 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的椎骨组成，大小不等。因此，尾部 高度进化的，可能代表整个中轴骨骼中使用的模块化生长控制机制。 在密切相关的啮齿动物中尾部多样性的一个例子是小鼠（小家鼠）和 两足的较小的埃及跳鼠（Jaculus jaculus），从一个大约5000万的共同祖先分化而来 年前除了明显夸张的后肢，跳鼠还进化出了多种变化， 脊椎骨骼以支撑其直立姿势，包括各个脊椎元件的伸长。的 本申请的目的是确定小鼠椎骨生长的时间和细胞参数 和跳鼠，然后使用候选人和公正的方法来调查分子机制， 是椎骨生长速度差异的基础。我们假设基因表达和控制的局部变化 一块骨头比另一块长得多或少的能力。这一假设将在追求三个测试 具体目标：1）定义建立和变化的椎骨生长的时间和细胞参数 比例，2）揭示利钠肽信号传导驱动椎骨生长和差异伸长的作用 研究与椎骨不成比例生长相关的基因表达差异。这些目标 将使用在我的实验室或通过合作建立的方法进行追踪，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 合理的实验方法的优势，以了解自然发生的椎骨变异， 表型与传统模型系统中观察到的表型不同，这些研究的意义 在于有机会打开一个相对未开发的骨骼生物学领域， 了解身体比例的发展和演变。