CAREER: Probing Specificity and Competition in the Lipid Droplet Proteome

脂滴是细胞内能量储存和脂类分布的枢纽。因此，它们在从肥胖和糖尿病到动脉粥样硬化和肝脏疾病等广泛的健康问题上发挥着核心作用。这项研究旨在了解蛋白质如何与脂滴特异性结合，以控制其生命周期和代谢结果。多尺度模拟和协同合作实验将被用来询问具有不同中性脂质成分的脂滴的选择性靶向和响应代谢条件的特定靶向背后的机制，例如过度的能量储存或饥饿。我们还将探索两种新的潜在调控机制：动力学选择和通过改变表面性质的变构蛋白结合。这项研究的学术价值将是促进我们对LD生物学的理解，而更广泛的影响将是建立一个基础，以帮助指导未来的治疗干预。此外，LDS是来自微生物的可持续脂肪产品的生产中心。因此，在酵母和真核系统中获得的见解将与微生物系统有关，以帮助开发气候解决方案，如可扩展的生物燃料和生物塑料生产。与这些目标紧密结合，该教育计划将使大量一年级和二年级本科生在一系列气候解决方案中接触到化学、物理和生物学，例如脂滴在生物塑料和生物能源生产中的作用。脂滴(LDS)是中性脂类(NL)存储细胞器，在能量代谢和脂类分布中发挥核心作用。它们独特地被磷脂单分子层包围，上面装饰着一系列动态的蛋白质。这项拟议的研究旨在探索LD蛋白质组的调控机制。一套多尺度模拟方法和协调的实验合作将解决：1)蛋白质如何根据其NL组成选择性地靶向某些LDS池；2)胞质蛋白质如何基于代谢条件特异性靶向；以及3)变构和/或动力学选择是否影响蛋白质竞争。此外，还将开发多种方法进步，以增强我们通过模拟研究LDS和蛋白质-单层相互作用的能力。如果成功，这项拟议的研究将促进我们对LD生物学及其如何影响代谢紊乱和疾病，如肥胖、糖尿病、肝病和动脉粥样硬化的理解。此外，LDS是来自微生物的可持续脂肪产品的生产中心。因此，在酵母和真核系统中获得的见解将与微生物系统有关，以帮助开发气候解决方案，如可扩展的生物燃料和生物塑料生产。与这些目标紧密结合，该教育计划将使大量一年级和二年级本科生接触一系列气候解决方案中的化学、物理和生物学，例如LDS在生物塑料和生物能源生产中的作用。该奖项反映了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。

Lipid droplets (LD) are the cellular hubs of energy storage and lipid distribution. As such they play a central role in a wide range of health issues from obesity and diabetes to atherosclerosis and liver diseases. This research aims to understand how proteins specifically bind to lipid droplets to control their lifecycle and metabolic outcomes. Multiscale simulations and coordinated collaborative experiments will be used to query the mechanisms behind selective targeting of lipid droplets with different neutral lipid compositions and specific targeting in response to metabolic conditions, such as excess energy storage or starvation. We will also probe two new potential mechanisms of regulation: kinetic selection and allosteric protein association through altered surface properties. The intellectual merit of this research will be advancing our understanding of LD biology, while the broader impacts will be establishing a foundation to help guide future therapeutic interventions. Additionally, LDs are the production hubs of sustainable lipid products from microbes. Thus, insights gained in yeast and eukaryotic systems will be related to microbial systems to aid in the development of climate solutions, such as scalable biofuel and bioplastic production. Closely integrated with these goals, the educational plan will expose large numbers of first and second-year undergraduates to chemistry, physics, and biology in an array of climate solutions, featuring as an example the role of lipid droplets in bioplastic and bioenergy production.Lipid droplets (LDs) are neutral lipid (NL) storage organelles that play a central role in energy metabolism and lipid distribution. They are uniquely surrounded by phospholipid monolayers decorated with a dynamic array of proteins. The proposed research aims to probe the mechanisms that regulate the LD proteome. A suite of multiscale simulation methods and coordinated experimental collaborations will address: 1) how proteins selectively target certain pools of LDs based on their NL composition; 2) how cytosolic proteins specifically target based on metabolic conditions; and 3) if allostery and/or kinetic selection influence protein competition. Multiple methodological advances will additionally be developed to enhance our ability to study LDs and protein-monolayer interactions through simulations. If successful, the proposed research will advance our understanding of LD biology and how it influences metabolic disorders and diseases, such as obesity, diabetes, liver disease, and atherosclerosis. Additionally, LDs are the production hubs of sustainable lipid products from microbes. Thus, the insights gained in yeast and eukaryotic systems will be related to microbial systems to aid the development of climate solutions, such as scalable biofuel and bioplastic production. Closely integrated with these goals, the educational plan will expose large numbers of first and second-year undergraduates to chemistry, physics, and biology in an array of climate solutions, featuring as an example the role of LDs in bioplastic and bioenergy production.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.