New Chemical Tools for Advancing Lipid Metabolic Labeling

在化学系生命过程化学（CLP）项目的支持下，来自田纳西大学诺克斯维尔分校的Michael Best和托德雷诺兹教授及其研究小组正在研究化学探针的开发，这些探针能够检测，跟踪和成像细胞中特定脂质分子的产生。脂质控制许多关键的生物过程，因此脂质生物合成的失调导致包括癌症在内的严重疾病。尽管如此，由于膜的复杂性和不断发生相互转化的脂质结构的多样性，跟踪细胞中脂质的产生和定位仍然具有挑战性。通过该项目，将设计新的策略，通过开发渗透脂质生物合成的探针来克服这些长期存在的障碍，以产生便于检测的脂质产物的标记版本。这项工作将使研究人员能够在一个跨学科的环境中进行密集培训，其中包括从化学到生物学的各种元素。此外，还将通过旨在提高大学预科学生对研究的理解和热情的外展工作来扩大研究的参与。在该项目中，正在开发带有小型可点击标签的脂质生物合成前体的探针类似物，以渗透正常的细胞机器并产生标记的脂质产物。这些分子通过生物正交反应的后衍生化预计能够附着各种报告标签，这将有助于跟踪细胞中的脂质生物合成。正在采取不同的方法来推进脂质代谢物标记的方法。一方面，正在开发探针以能够标记特异性和重要的脂质靶标。在一个互补的方法，探针策略正在设计用于标记更大的脂质家族，以更广泛地分析脂质代谢。在这些情况下，我们的目标是合成新的探针类似物的代谢前体，并将它们的标记特性进行全面的评价，包括通过荧光显微镜细胞标记的分析，使用多种技术的标记脂质的身份验证，并确定探针的细胞毒性。此外，脂质代谢标记可以通过使用靶向部分将探针定向到特定的细胞器来推进。这种方法可以提供新的化学工具来解决重要的生物学问题，这些问题涉及脂质在关键生物过程中合成、运输和失调的方式。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知识价值和更广泛的影响审查标准进行评估来支持。

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.