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，诺克斯维尔田纳西大学的Michael Best教授和Todd Reynolds教授及其研究小组正在研究开发能够检测、跟踪和成像细胞中特定脂质分子产生的化学探针。脂类控制着许多关键的生物学过程，因此，脂类生物合成的失调会导致包括癌症在内的严重疾病。尽管有这一重要意义，但由于细胞膜的复杂性和不断发生相互转化的脂类结构的多样性，追踪细胞内脂类的产生和定位仍然具有挑战性。通过这个项目，将设计新的战略来克服这些长期存在的障碍，方法是开发渗透到脂质生物合成中的探针，以生产便于检测的脂质产品的标记版本。这项工作将使研究人员能够在包含从化学到生物学的各种元素的跨学科环境中进行密集培训。此外，将通过旨在提高预科学生对研究的理解和热情的外展努力来扩大对研究的参与。在这个项目中，正在开发带有微小可点击标记的脂质生物合成前体的探针类似物，以渗透到正常的细胞机械中并生产标记的脂质产品。通过生物正交反应对这些分子进行后衍生化有望实现各种报告标签的附着，从而促进细胞内脂质生物合成的跟踪。目前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，以便能够标记特定和重要的脂类靶标。在一种补充方法中，正在设计探针策略来标记更大的脂类家族，以更广泛地分析脂类代谢。在每一种情况下，目标都是合成新的代谢前体探针类似物，并对其标记性质进行全面评估，包括通过荧光显微镜分析细胞标记，使用多种技术验证标记脂质的身份，以及测定探针的细胞毒性。此外，通过使用靶向部分将探针定向到特定的细胞器，可以推进脂代谢标记。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，这些问题涉及关键生物过程中脂质的合成、贩运和失调的方式。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。

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.