CAREER: Probing Specificity and Competition in the Lipid Droplet Proteome

脂滴（LD）是细胞能量储存和脂质分布的枢纽。因此，它们在肥胖、糖尿病、动脉粥样硬化和肝脏疾病等一系列健康问题中发挥着核心作用。本研究旨在了解蛋白质如何特异性地与脂滴结合以控制其生命周期和代谢结果。多尺度模拟和协同实验将用于查询脂滴选择性靶向背后的机制，脂滴具有不同的中性脂成分和特异性靶向，以响应代谢条件，如能量储存过剩或饥饿。我们还将探讨两种新的潜在调节机制：动力学选择和通过改变表面性质的变构蛋白结合。这项研究的智力价值将促进我们对LD生物学的理解，而更广泛的影响将为帮助指导未来的治疗干预奠定基础。此外，ld是微生物可持续脂质产物的生产中心。因此，在酵母和真核生物系统中获得的见解将与微生物系统相关，以帮助开发气候解决方案，例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的是，该教育计划将向大量一年级和二年级本科生展示一系列气候解决方案中的化学、物理和生物学，并以脂滴在生物塑料和生物能源生产中的作用为例。脂滴（ld）是中性脂质（NL）储存细胞器，在能量代谢和脂质分布中起核心作用。它们被磷脂单层独特地包裹着，磷脂单层被动态排列的蛋白质装饰着。本研究旨在探讨LD蛋白组的调控机制。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组成选择性地靶向特定的ld池；2)细胞质蛋白如何基于代谢条件特异性靶向；3)变构和/或动力学选择是否影响蛋白质竞争。此外，还将开发多种方法的进步，以提高我们通过模拟研究ld和蛋白质单层相互作用的能力。如果成功，这项研究将推进我们对LD生物学的理解，以及它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。此外，ld是微生物可持续脂质产物的生产中心。因此，在酵母和真核生物系统中获得的见解将与微生物系统相关，以帮助开发气候解决方案，例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的是，该教育计划将向大量一年级和二年级本科生展示一系列气候解决方案中的化学、物理和生物学，并以lld在生物塑料和生物能源生产中的作用为例。该奖项反映了美国国家科学基金会的法定使命，并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，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.