Collaborative Research: NSF-BSF: How cell adhesion molecules control neuronal circuit wiring: Binding affinities, binding availability and sub-cellular localization

合作研究：NSF-BSF：细胞粘附分子如何控制神经元电路布线：结合亲和力、结合可用性和亚细胞定位

• 批准号: 2321480
• 负责人: Barry Honig
• 金额: $ 80万
• 依托单位: Columbia University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2321480&HistoricalAwards=false
• 关键词: Collaborative; Research; NSF; BSF; How

The sensory and motor functions of the nervous system depend on the establishment of precise connections between different types of neurons and target cells during development. In the developing nervous systems of both vertebrates and invertebrates, neurons express a wide diversity of cell adhesion molecules, which mediate interactions that are essential for specifying target selection and connectivity patterns. This proposal will study the molecular control of circuit development through a combination of genetic and biophysical approaches in which binding affinities and cell surface localization of cell adhesion molecules are manipulated and their effects on neural circuit formation are studied in the larva fruit fly. The proposed research will have a significant impact on multiple research fields due to the generality of the phenomena to be studied. Moreover, integrating computational and structural biology with developmental neuroscience is likely to stimulate similar collaborative efforts in these fields. In terms of training, students and postdocs working on this project will develop a deep appreciation of both computational and experimental work, thus providing exemplars for broadly trained interdisciplinary scientists. Women scientists constitute over 50% of the participating groups. The research program includes training of high school and undergraduate students, many of whom are from underrepresented minorities in sciences, through summer internships. The team will continue partnering with a network of high schools across lower-income districts and minority serving colleges, and run the DREAM-High cloud computing course for high school students that increases student awareness of and interest in biological sciences, empowers students to adopt scientific reasoning and critical-thinking skills, and inspires students to seek post-secondary education in related fields.This project will investigate the effects of binding affinity and cell surface availability of cell adhesion molecules (CAMs) on circuit formation in Drosophila. The study will focus on the larval neuromuscular system and mushroom body development. At the molecular level, the focus will be on two interacting groups of CAMs, the Dprs (Defective in Proboscis extension Response) and the DIPs (Dpr Interacting Proteins). The choice of these proteins and anatomical structures is based on the deep understanding of the biophysical properties of DIPs and Dprs that has emerged over the past few years, and on the demonstration of their crucial roles in the development of these anatomical structures. Here, by examining various Dpr/DIP cognate pairs in different neurodevelopmental settings, the findings should deepen currently limited knowledge of the in vivo consequences of altering avidity using both changes in binding affinities and in expression levels. A particular focus will be on the phenomenon of cis inhibition, whereby interactions between cognate binding partners on the same cell compete with trans binding to partners on apposed cells. The underlying hypothesis is that cis-inhibition is a key regulatory mechanism in neural development.This project is jointly funded by the Neural Systems Cluster in IOS and the Molecular Biophysics Cluster in MCB of the Directorate for Biological Sciences.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.

神经系统的感觉和运动功能依赖于在发育过程中不同类型的神经元和靶细胞之间建立精确的联系。在脊椎动物和无脊椎动物发育的神经系统中，神经元表达各种各样的细胞黏附分子，这些黏附分子调节相互作用，这些相互作用对于指定靶点选择和连接模式是必不可少的。这项建议将通过遗传学和生物物理相结合的方法来研究细胞黏附分子的结合亲和力和细胞表面定位的分子控制，并研究它们对果蝇幼虫神经回路形成的影响。由于所研究现象的普遍性，所提出的研究将对多个研究领域产生重大影响。此外，将计算和结构生物学与发育神经科学相结合，可能会刺激这些领域的类似合作努力。在培训方面，从事该项目的学生和博士后将对计算和实验工作产生深刻的欣赏，从而为受过广泛培训的跨学科科学家提供范例。女科学家占参与群体的50%以上。该研究计划包括通过暑期实习培训高中生和本科生，其中许多人来自科学界代表性较低的少数族裔。该团队将继续与低收入地区和少数族裔服务大学的高中网络合作，并为高中生开设梦想-高级云计算课程，以提高学生对生物科学的认识和兴趣，增强学生采用科学推理和批判性思维的技能，并激励学生寻求相关领域的高等教育。该项目将调查细胞黏附分子(CAM)的结合亲和力和细胞表面可用性对果蝇电路形成的影响。这项研究将集中在幼虫的神经肌肉系统和蘑菇体的发育上。在分子水平上，重点将放在两组相互作用的CAMs上，dprs(鼻子延伸反应缺陷)和DIPS(dpr相互作用蛋白)。选择这些蛋白质和解剖结构是基于对过去几年出现的DIPs和DPRs的生物物理性质的深入了解，以及对它们在这些解剖结构发展中的关键作用的展示。在这里，通过研究不同神经发育环境中的各种DPR/DIP同源对，这些发现应该深化目前有限的知识，即通过结合亲和力和表达水平的变化来改变亲和力的体内后果。将特别关注顺式抑制现象，即同一细胞上同源结合伙伴之间的相互作用与与相反细胞上的伙伴的反式结合竞争。潜在的假设是顺式抑制是神经发育中的关键调控机制。该项目由IOS的神经系统集群和生物科学局MCB的分子生物物理学集群共同资助。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。