New Chemical Tools for Advancing Lipid Metabolic Labeling

促进脂质代谢标记的新化学工具

• 批准号: 2310263
• 负责人: Michael Best
• 金额: $ 42.15万
• 依托单位: University of Tennessee Knoxville
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2310263&HistoricalAwards=false
• 关键词: New; Chemical; Tools; Advancing; Lipid

With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professors Michael Best and Todd Reynolds from the University of Tennessee, Knoxville and their research groups are studying the development of chemical probes that enable detection, tracking, and imaging of the production of specific lipid molecules in cells. Lipids control many critical biological processes and therefore dysregulation of lipid biosynthesis results in severe diseases including cancer. Despite this significance, tracking the production and localization of lipids in cells remains challenging due to the complexity of membranes and the diversity of lipid structures that are constantly undergoing interconversion. Through this project, new strategies will be designed to overcome these longstanding obstacles by developing probes that infiltrate lipid biosynthesis to produce tagged versions of lipid products that facilitate their detection. This work will enable intensive training of researchers in an interdisciplinary environment that incorporates elements ranging from chemistry to biology. Additionally, participation in research will be broadened through outreach efforts aimed at enhancing understanding and enthusiasm for research among pre-collegiate students.In this project, probe analogues of lipid biosynthetic precursors bearing diminutive clickable tags are being developed to infiltrate normal cellular machinery and produce labeled lipid products. Post-derivatization of these molecules through bioorthogonal reactions is expected to enable the attachment of a variety of reporter tags that will facilitate tracking of lipid biosynthesis in cells. Distinct approaches are being undertaken to advance the approach of lipid metabolite labeling. On one hand, probes are being developed to enable labeling of specific and important lipid targets. In a complementary approach, probe strategies are being devised for labeling larger families of lipids to analyze lipid metabolism more broadly. In each of these cases, the goal is to synthesize new probe analogues of metabolic precursors and subject them to comprehensive evaluation of their labeling properties, including analysis of cellular labeling through fluorescence microscopy, validation of the identities of labeled lipids using multiple techniques, and determination of probe cytotoxicity. Furthermore, lipid metabolic labeling could be advanced by directing probes to specific cellular organelles using targeting moieties. This approach could provide new chemical tools for addressing important biological questions regarding the manner in which lipids are synthesized, trafficked, and dysregulated during crucial biological processes.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.

在田纳西大学，诺克斯维尔大学及其研究小组的迈克尔·贝斯特（Michael Best）和托德·雷诺（Michael Best）和托德·雷诺兹（Todd Reynolds）的支持下，诺克斯维尔大学（Knoxville）及其研究小组正在研究化学探针的开发，这些化学探针的开发可实现细胞中特定脂质分子的产生。脂质控制着许多关键的生物学过程，因此脂质生物合成的失调导致包括癌症在内的严重疾病。尽管有这种意义，但由于膜的复杂性以及不断经历相互转换的脂质结构的多样性，跟踪细胞中脂质的生产和定位仍然具有挑战性。通过该项目，将设计新的策略来克服这些长期存在的障碍，从而通过开发浸润脂质生物合成的探针来生产具有促进其检测的脂质产品的标记版本。这项工作将在跨学科环境中对研究人员进行深入培训，该跨学科环境结合了从化学到生物学的元素。此外，通过旨在增强学前学生研究的理解和热情的外展工作将扩大研究的参与。在该项目中，正在开发出脂质生物合成前体的探针类似物，该探针类似物正在开发出可单击的单击标签，以浸入正常的细胞机械和生产标记的Lipid产品。这些分子通过生物正交反应的衍生后有望使各种记者标签的附着，这些标签将有助于跟踪细胞中脂质生物合成。正在采取不同的方法来推进脂质代谢产物标记的方法。一方面，正在开发探针以实现特定和重要脂质靶标的标记。在一种补充方法中，正在设计探测策略，用于标记较大的脂质家族，以更广泛地分析脂质代谢。在每种情况下，目标是合成代谢前体的新探针类似物，并对它们的标记特性进行全面评估，包括通过荧光显微镜对细胞标记进行分析，使用多种技术标记脂质的识别率的验证，并确定探针细胞毒性。此外，可以通过使用靶向部分将探针引导到特定的细胞细胞器来提出脂质代谢标记。这种方法可以提供新的化学工具来解决有关在关键生物学过程中合成，贩运和失调方式的重要生物学问题。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子和更广泛影响的审查标准来通过评估来通过评估来支持的。