Saxophone: A glucose-sensitive type I Dpp/BMP receptor

萨克斯管：葡萄糖敏感的 I 型 Dpp/BMP 受体

• 批准号: 2127540
• 负责人: Anthea Letsou
• 金额: $ 81.21万
• 依托单位: University of Utah
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2127540&HistoricalAwards=false
• 关键词: Saxophone; glucose; sensitive; type; Dpp

Discoveries made in the fruit fly Drosophila melanogaster concerning how signaling pathways are built and how those pathways are controlled by metabolic signals provide a foundation for understanding developmental abnormalities that arise due to both an environmental and genetic component. In particular, recent breakthrough studies linked fruit fly fertility to its nutritive environment. In conditions of low glucose, female fruit flies have 35% fewer progeny, with reduced fertility resulting from a high rate of embryonic lethality. Molecular studies revealed the Saxophone (Sax) receptor to be the metabolite-sensitive point of a signaling pathway that is essential for proper embryonic development (in this case the Bone Morphogenetic Protein or BMP signaling pathway). The current study will employ genetic (mutant analysis), molecular (sequence analysis), and biochemical (mass spectrometry) methods to probe: 1) the mechanism of metabolite-mediated regulation of Sax, and 2) the pathway’s evolutionary history. This multipronged and multidisciplinary study will also provide an integrative platform for educating students from middle school to graduate school in modern research methods. Inclusion of students from Salt Lake Center for Science Education (SLCSE), a magnet school in Salt Lake City serving a high proportion of economically disadvantaged (40%) and minority (48%) students in grades 8-12, in the research program is expected to contribute to improved science self-efficacy and facilitate retention of underserved student populations in science, technology, engineering, and mathematics (STEM). Activation and inhibition of BMP (Bone Morphogenetic Protein) signaling pathways at the right time and place is essential for all animal life, with defects in signaling leading to devastating abnormalities. Importantly, the breakthrough finding in Drosophila that O-linked-N-acetylglucosaminylation (O-GlcNAcylation) regulates Dpp (Decapentaplegic, a Drosophila BMP) signal transduction reveals new avenues for studies of the relationship of the environment to emergent developmental and physiological systems. In this project, the relationship of O-GlcNAcylation to Dpp signaling during development is assessed in the genetically tractable fruit fly model. Tests of the hypothesis that O-linked beta-N-acetylglucosamine (O-GlcNAc) regulates a nutrient-sensitive branch of the BMP/Dpp signaling family are central to the proposed research, and three lines of investigation are undertaken. First is a determination of how O-GlcNAc modifies the type 1 Dpp receptor Saxophone (Sax). Second is a determination of how bioactivities of the Thickveins (Tkv) and Sax type 1 receptors differ. Last is a determination of whether the nutrient-sensitive Sax arm of the Drosophila Dpp receptor pathway is conserved. The research proposed here will be used to introduce students from middle school to graduate levels to model systems genetic research. Establishment of long-term mentor-student relationships, especially with students from SLCSE (Salt Lake Center for Science Education), a magnet school in Salt Lake City serving a high proportion of economically disadvantaged (40%) and minority (48%) students in grades 8-12, is expected to improve science citizenship, trust, and scholarship, and facilitate student success in attaining independent STEM cell careers.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.

在果蝇果蝇中关于信号通路如何构建以及这些通路如何受代谢信号控制的发现为理解由于环境和遗传因素引起的发育异常奠定了基础。特别是，最近的突破性研究将果蝇联系起来。在低葡萄糖条件下，雌性果蝇的后代减少 35%，胚胎致死率较高，导致生育能力下降。对胚胎正常发育至关重要的信号通路的代谢物敏感点（在本例中为骨形态发生蛋白或 BMP 信号通路）当前的研究将采用遗传（突变分析）、分子（序列分析）和生物化学（质量分析）。光谱法）方法来探讨：1）代谢物介导的 Sax 调节机制，以及 2）该途径的进化历史。这项多管齐下、多学科的研究也将为教育学生提供一个综合平台。将盐湖科学教育中心 (SLCSE) 的学生从初中到研究生纳入现代研究方法，这是盐湖城的一所磁石学校，为高比例的经济困难学生 (40%) 和少数族裔 (48%) 学生提供服务。在 8-12 年级，该研究项目预计将有助于提高科学自我效能，并促进科学、技术、工程和数学 (STEM) 领域服务不足的学生群体保留 BMP（骨形态发生蛋白）的激活和抑制。信号通路在正确的时间和地点对所有动物的生命都至关重要，信号通路的缺陷会导致毁灭性的异常。果蝇 BMP）信号转导揭示了研究环境与新兴发育和生理系统关系的新途径。在遗传易处理的果蝇模型中评估了发育过程中 O-GlcNAc 信号转导对 Dpp 信号传导的影响。O-连接 β-N-乙酰葡萄糖胺 (O-GlcNAc) 调节 BMP/Dpp 信号传导家族的营养敏感分支这一假设的检验是。该研究的核心是，进行了三方面的研究，首先是确定 O-GlcNAc 如何修饰 1 型 Dpp 受体萨克斯管 (Sax)。确定粗静脉 (Tkv) 和 Sax 1 型受体的生物活性有何不同。最后是确定果蝇 Dpp 受体途径的营养敏感 Sax 臂是否保守。此处提出的研究将用于向学生介绍。从初中到研究生，再到模型系统遗传学研究，特别是与盐湖城一所磁石学校 SLCSE（盐湖科学教育中心）的学生建立长期的师生关系。 8-12 年级经济弱势群体 (40%) 和少数族裔 (48%) 学生比例较高，预计将提高科学公民意识、信任和学术水平，并促进学生成功获得独立的 STEM 细胞职业生涯。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。