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CAREER: The genetic and developmental basis of body size evolution in nematodes

职业：线虫体型进化的遗传和发育基础

基本信息

批准号：
2238788
负责人：
Gavin Woodruff
金额：
$ 96.48万
依托单位：
University of Oklahoma Norman Campus
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2028-02-29
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2238788&HistoricalAwards=false
关键词：
CAREER genetic developmental basis body

项目摘要

The diversity among animal body sizes (from at least ants to elephants) is immense and demands explanation. Yet, the genetic and developmental changes that cause body size evolution remain unknown. The proposed work aims to address this problem by harnessing both long-established and cutting-edge genetic techniques in closely-related roundworm species with drastically different body sizes to identify the causes of body size variation. This work is important because we know larger roundworm species have larger cells than those of smaller species, and when the processes regulating cell size go awry, diseases such as cancer emerge. This work then has the potential to discover novel genes that control cell size and thus potential novel targets for cancer therapeutics. Beyond this, the research work described above will be integrated with multiple, established educational initiatives in the state of Oklahoma including: 1) The University of Oklahoma’s four-year undergraduate research experience program; 2) A multi-year summer research program for American Indian undergraduates; 3) A research experience for high school students summer program; and 4) A graduate-student led summer coding workshop. Additionally, an undergraduate developmental biology laboratory course will be developed where students will participate in the original research activities described above. The proposed work not only aims to make significant advances in understanding the evolution of body size and the genes underlying cell size variation, but this work also aims to connect multiple educational efforts with these research efforts to simultaneously advance both scientific knowledge and societal good.Understanding how developmental systems evolve to promote phenotypic diversity is a fundamental goal of biology. These systems include and regulate the morphogenetic fields, signaling factors, and differentiation decisions essential for the construction and ultimate form of a multicellular organism. Despite this, while gene regulatory networks have been painstakingly described in a handful of model systems, network architecture change is rarely connected to morphological divergence among species. How does genetic variation change developmental processes to cause divergent phenotypes? Over forty years of C. elegans genetics has revealed the developmental details of a canonical TGF-β signaling network that regulates body size in this species. C. inopinata is the sister species of C. elegans, and it is nearly twice as long in size as its highly-studied close relative. Here, the vast background knowledge of a long-standing model system will be integrated with a comparative approach to understand how network modification causes phenotypic divergence. This work will include: 1) The perturbation of TGF-β pathway activity in two species to determine how ancestral body size genes evolve to promote cell size divergence; 2) The generation and mapping of large-effect body size mutations in C. inopinata to discover novel genes driving cell size regulation; and 3) The characterization of tissue-specific cell size variation in mutants across development in two species. Not only will this work map genotypes to organismal phenotypes such as body size, but it will also show how genotypes influence cellular phenotypes to cause the emergence of such organismal phenotypes. The research work described above will be integrated with multiple, established educational initiatives in the state of Oklahoma to broaden the participation of students at all levels in scientific research.This project is jointly funded by the BIO-IOS-Developmental Systems Program and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

动物体型（至少从蚂蚁到大象）的差异是巨大的，需要解释。然而，导致身体大小进化的遗传和发育变化仍然未知。这项拟议的工作旨在通过利用长期建立和尖端的遗传技术来解决这个问题，这些技术用于密切相关的蛔虫物种，这些物种的身体大小截然不同，以确定身体大小变化的原因。这项工作很重要，因为我们知道较大的线虫物种比较小物种的细胞更大，当调节细胞大小的过程出现问题时，就会出现癌症等疾病。这项工作有可能发现控制细胞大小的新基因，从而发现癌症治疗的潜在新靶点。除此之外，上述研究工作将与俄克拉荷马州的多个既定教育计划相结合，包括：1）俄克拉荷马州大学的四年制本科研究经验计划; 2）美国印第安本科生的多年夏季研究计划; 3）高中生夏季计划的研究经验;和4）研究生领导的夏季编码研讨会。此外，将开发本科生发育生物学实验室课程，学生将参与上述原始研究活动。这项工作的目的不仅是在理解身体大小的进化和细胞大小变异的基因方面取得重大进展，而且这项工作还旨在将多项教育工作与这些研究工作联系起来，同时促进科学知识和社会利益。了解发育系统如何进化以促进表型多样性是生物学的一个基本目标。这些系统包括并调节形态发生领域，信号传导因子和分化决定，这些对于多细胞生物体的构建和最终形式至关重要。尽管如此，虽然基因调控网络已经在少数模型系统中被精心描述，但网络结构的变化很少与物种之间的形态差异有关。遗传变异是如何改变发育过程从而导致不同的表型的？40多年来，C。elegans遗传学揭示了一个典型的TGF-β信号网络的发育细节，该网络调节该物种的体型。C. inopinata是C.它的体型几乎是其高度研究的近亲的两倍。在这里，一个长期存在的模型系统的大量背景知识将与比较方法相结合，以了解网络修饰如何导致表型分化。这项工作将包括：1）两个物种中TGF-β通路活性的扰动，以确定祖先体型基因如何进化以促进细胞大小分化; 2）C. inopinata发现驱动细胞大小调节的新基因;和3）在两个物种的发育过程中突变体中组织特异性细胞大小变化的表征。这项工作不仅将基因型映射到生物表型，如身体大小，而且还将显示基因型如何影响细胞表型，从而导致这种生物表型的出现。上述研究工作将与多个，在俄克拉荷马州建立了教育计划，以扩大各级学生对科学研究的参与。该项目由BIO-IOS-发展系统计划和刺激竞争研究的既定计划（EPSCoR）共同资助该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。