CAREER: Molecular control of differentiation in the enteric nervous system

该奖项的全部或部分资金来自《2021年美国救援计划法案》(公法117-2)。肠道神经系统(ENS)--“肠道中的大脑”--调节着重要的胃肠道功能，如消化和营养吸收。为了完成这一角色，需要在发育过程中组装一个由特定细胞类型-神经细胞和神经胶质细胞-组成的复杂网络。调控这些不同细胞类型产生的遗传因素以及它们在发育过程中形成的电路目前还知之甚少。也不知道肠道不同区域(例如，胃和肠)的电路是使用不同的信号构建的，还是沿着整个肠道使用相同的发育信号。这个项目将提供对肠道神经系统如何发展的基本见解，以及肠道神经回路与周围组织之间的相互作用。了解肠道神经细胞类型是如何产生的，对于更好地理解这些神经细胞如何调节肠道生理和功能也是至关重要的。除了它的科学目标，这个项目还将为本科生提供广泛的实践研究经验，特别强调来自历史上在生物学研究中代表性不足的群体的学生，通过1)一个关于基因组编辑的新的研究密集型本科课程，以及2)从第一年开始为本科生组织研究经验。为研究生和博士后研究人员提供更多的培训机会，以及旨在通过在区域科学博览会上的互动摊位展示斑马鱼在神经科学方面的研究优势来提高科学素养的公共推广活动。尽管ENS在肠道发育和功能中起着关键作用，但对于控制ENS神经元发育的基因和基本原理，人们的认识还存在很大差距。每个肠道细分都有特定的功能--相应地，ENS还显示了肠道沿线的区域分子和细胞差异。一个基本但仍未检验的问题是，在多大程度上，ENS的神经发生受到每个肠道分区内特定区域程序的调控。解决这个问题对于全面了解神经发生的核心原理以及更好地了解神经如何与周围的肠道细胞协调发展至关重要。该项目将在一系列实验中确定特定区域的基因活动及其调控计划。第一组将阐明控制区域特异性ENS神经发生的分子机制。第二组将使用表观基因组和转录图谱来识别特定地区的调控程序，以检测和功能测试调控成分。第三组将通过使用CRISPR基因组编辑管道来评估选定转录因子基因的区域特定功能，从而发现区域特定调控程序控制ENS神经发生的程度。这项工作将显著扩展关于控制神经发生的基因和调控程序的知识，并通过开发新的CRISPR基因组编辑课程和PI实验室的独立科学研究为本科生提供研究经验。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).The enteric nervous system (ENS) – the “brain in the gut” – regulates important gastrointestinal tract functions such as digestion and nutrient uptake. To fulfill this role, a complex network of specific cell types – nerve cells and glial cells – need to be assembled during development. The genetic factors that regulate the generation of these different cell types and the circuits they form during development are poorly understood. It is also not known if the circuits in distinct regions of the gut (for example, the stomach and intestine), are constructed using different signals, or if the same developmental signals are used along the whole length of the gut. This project will provide fundamental insights into how the enteric nervous system develops, and the interactions between the neural circuits of the gut and surrounding tissues. Understanding how gut neural cell types get generated is also essential for a better comprehension of how these nerve cells regulate gut physiology and function. In addition to its scientific goals, this project will also provide extensive, hands-on research experiences for undergraduate students, with a particular emphasis on students from groups who have been historically underrepresented in biological research, through 1) a new research-intensive undergraduate course on genome editing and 2) organized research experiences for undergraduates starting in their first year. Additional training opportunities are provided for graduate students and postdoctoral researchers, as well as public outreach activities that aim to increase scientific literacy by showcasing the advantages of zebrafish research in neuroscience via interactive booths at regional science fairs.The ENS is the largest part of the peripheral nervous system providing the intrinsic innervation of the gut. Despite the critical role of the ENS for gut development and function, there is a significant gap in knowledge regarding the genes and fundamental principles that control ENS neuronal development. Each gut subdivision has specific functions – accordingly, the ENS also shows regional molecular and cellular differences along the gut. A fundamental yet unexamined question that remains is the degree to which ENS neurogenesis is regulated by region-specific programs within each gut subdivision. Addressing this question is essential for a complete understanding of the core principles that underlie ENS neurogenesis, as well as a better understanding of how the ENS develops in concert with surrounding gut cells. This project will determine region-specific gene activities and their regulatory programs in sets of experiments. The first set will elucidate molecular mechanisms that control region-specific ENS neurogenesis. The second set will identify region-specific regulatory programs using epigenomic and transcriptomic profiling to detect and functionally test regulatory components. The third set will discover the extent to which region-specific regulatory programs control ENS neurogenesis by using a CRISPR genome editing pipeline to assess the region-specific function of selected transcription factor genes. This work will significantly expand knowledge about the genes and regulatory programs that control ENS neurogenesis, as well as provide research experiences for undergraduates through developing a new CRISPR genome editing course and independent scientific research in the PI’s lab.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.