The Role of Lipids in Different Cell Fates

这个项目将为脂质在细胞生物学中的作用提供新的线索。脂类形成屏障，定义细胞及其内部隔间。它们最近也被认为是作为信号分子的关键角色，调节细胞过程。现在很清楚的是，细胞产生成千上万种具有不同功能的独特的脂类。然而，这些脂类的个体功能仍不清楚。在此背景下，该项目应用最先进的化学生物学和分析方法来研究特定脂类在不同细胞命运中的作用。通过这样做，这项研究将揭示基本细胞过程背后的新机制。这个项目采用了综合的方法工具，可以在教育领域培训一支具有全球竞争力的劳动力队伍，让代表不足的学生群体和教师参与研究和科学研究。本项目将阐明脂质在细胞死亡过程中的作用，提供对不同类型的程序性细胞死亡的更好的基本了解，这是涉及维持细胞动态平衡的生理关键过程。这些目标将使用一套综合的方法来实现，该方法将脂类组学、转录组学和蛋白质组学与结构特定的生物正交脂类探针相结合。这项研究计划将重点放在i)基于其结构的不同神经酰胺在细胞凋亡过程中的功能，以及ii)超长链脂肪酸在坏死性下垂时膜通透性中的作用。这些研究将使用两组分整合：i)确定不同神经酰胺合成酶的底物特异性，并使用结构特异性探针和遗传扰动来研究特定神经酰胺的功能；ii)确定极长链脂肪酸在坏死性下垂过程中的定位和相互作用伙伴。这些目标将阐明脂质在细胞死亡过程中的作用，为更好地从根本上理解这些生理关键过程提供依据。这项工作的结果将阐明基于特定脂类的精确化学结构的功能作用。他们将专门阐明单个神经酰胺和脂肪酸在膜通透性中的作用，以及它们在细胞凋亡和坏死性下垂过程中与其他生物分子的相互作用。这一知识将为研究结构特异性对细胞内脂质功能的影响的新研究打开大门。这一奖项反映了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 project will shed new light on the role of lipids in cell biology. Lipids form barriers that define cells and their internal compartments. They are also recently recognized for their critical roles as signaling molecules, regulating cellular processes. It is now clear that cells produce thousands of unique lipid species with diverse functions. However, the individual functions of these lipid species remain unclear. Within this context, this project applies state-of-the-art chemical biology and analytical approaches to investigate the role of specific lipids in different cell fates. By doing so, this study will reveal novel mechanisms underlying fundamental cellular processes. The comprehensive methodological tools employed in this project allows training a globally competitive workforce across the educational spectrum involving participation of underrepresented student groups and teachers in research and scientific inquiry.This project will elucidate the function of lipids during cell death, providing a better fundamental understanding of different types of programmed cell death, which are physiologically critical processes that are involved in maintaining cellular homeostasis. These goals will be achieved using an integrative set of approaches that merges lipidomics, transcriptomics, and proteomics with structure-specific bioorthogonal lipids probes. This research program will focus on i) the function of distinct ceramides based on their structure during apoptosis and ii) the role of very long chain fatty acids in permeabilization of the membranes during necroptosis. A two component integration will be used for these studies: i) Determine substrate specificity of different ceramide synthases and investigate the function of specific ceramides using structure-specific probes and genetic perturbations, ii) determine the localization and interaction partners of very long chain fatty acids during necroptosis. The objectives will elucidate the function of lipids during cell death, providing a better fundamental understanding of these physiologically critical processes. The results from this work will shed light on the functional roles of specific lipids based on their precise chemical structure. They will specifically elucidate the role of individual ceramides and fatty acids on membrane permeabilization and their interaction with other biomolecules during apoptosis and necroptosis. This knowledge will open the door to novel studies investigating the impact of structural specificity on lipid function in cells.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.