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Drosophila melanogaster中发现的关于信号通路是如何建立的以及这些通路是如何被代谢信号控制的，为理解由于环境和遗传因素引起的发育异常提供了基础。特别是，最近的突破性研究将果蝇的生育能力与其营养环境联系起来。在低葡萄糖的条件下，雌性果蝇的后代减少了35%，由于胚胎死亡率高，生育能力降低。分子研究表明，萨克斯管（萨克斯）受体是一个信号通路的代谢敏感点，这是必要的适当的胚胎发育（在这种情况下，骨形态发生蛋白或BMP信号通路）。目前的研究将采用遗传学（突变分析），分子（序列分析）和生物化学（质谱）方法来探测：1）代谢物介导的Sax调节机制，2）途径的进化历史。这种多管齐下和多学科的研究也将提供一个综合平台，教育学生从中学到研究生院的现代研究方法。从盐湖科学教育中心（SLCSE），在湖城的磁铁学校服务的高比例的经济困难（40%）和少数民族（48%）的学生在8-12年级的学生，在研究计划中的学生的包容性，预计将有助于提高科学自我效能，并促进在科学，技术，工程和数学（STEM）的服务不足的学生群体的保留。在正确的时间和地点激活和抑制BMP（骨形态发生蛋白）信号通路对所有动物的生命至关重要，信号缺陷会导致破坏性的异常。重要的是，在果蝇中的突破性发现，O-连接-N-乙酰氨基葡萄糖（O-GlcNAc）调节Dpp（Decapentaplegic，果蝇BMP）信号转导揭示了新的途径，研究环境的关系，紧急发展和生理系统。在该项目中，在遗传上易处理的果蝇模型中评估发育期间O-GlcNAc化与Dpp信号传导的关系。O-连接的β-N-乙酰葡糖胺（O-GlcNAc）调节BMP/Dpp信号家族的营养敏感分支的假设的测试是所提出的研究的核心，并进行了三条线的调查。首先是确定O-GlcNAc如何修饰1型Dpp受体Saxophone（Sax）。第二是确定Thickveins（TfS）和Sax 1型受体的生物活性如何不同。最后是确定果蝇Dpp受体途径的营养敏感性Sax臂是否保守。这里提出的研究将被用来介绍从中学到研究生水平的学生模型系统遗传学研究。建立长期的师生关系，特别是与SLCSE的学生（盐湖科学教育中心）是盐湖的一所磁铁学校，为8-12年级的高比例经济困难（40%）和少数民族（48%）学生提供服务，预计将提高科学公民意识、信任和奖学金，该奖项反映了NSF的法定使命，并被认为值得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来支持。