CAREER: Understanding the Immunometabolism-Epigenetic Crosstalk in Dendritic Cells

职业：了解树突状细胞中的免疫代谢-表观遗传串扰

• 批准号: 2412256
• 负责人: Abhinav Acharya
• 金额: $ 52.07万
• 依托单位: Case Western Reserve University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2412256&HistoricalAwards=false
• 关键词: CAREER; Understanding; Immunometabolism; Epigenetic; Crosstalk

Immune cells, which protect our body from diseases and disorders, need energy to function. Energy pathways can be manipulated by delivery of metabolites (substances involved in metabolism) which can act to modify immune cell function and metabolism. This CAREER project will utilize new synthesis techniques to generate nanoparticles of metabolites, which will then deliver these metabolites to specialized immune cells called dendritic cells, which are central to the initiation of primary immune responses. The work will advance understanding of energy metabolite-mediated changes in immune cells which can then be leveraged to generate robust immune responses against a variety of diseases including infections, cancer and inflammatory diseases. Additionally, under this project, a computer game will be designed to educate the player on various aspects of metabolism. This project will also engage undergraduate and graduate students and will highlight the importance of biomaterials, metabolism and immune system to the surrounding public community.Energy metabolism is a key player in all known diseases and disorders, (e.g. cancer and autoimmune diseases); however, there is a poor understanding of energy metabolite-mediated changes in immune cells at the epigenetic level (e.g. transcription factor and histone glycosylation/succinylation). The investigator’s long-term research goal is to study how the metabolite-based biomaterials control the function of immune cells at both epigenetic and functional levels. Towards this goal, the focus of this CAREER project is to understand the energy metabolite, transcription factor and functional protein axis in dendritic cells (DCs). The research presents a method for engineering particles that deliver metabolites to DCs in vitro and in vivo. This project will make engineering contributions by developing synthetic routes of metabolite-based nanoparticles that function as both carrier and cargo. Life science contributions will be made by identifying correlation between metabolites, transcription factors and epigenetic markers in DCs. Importantly, this project will determine the epigenetic changes in DCs due to succinylation/glycosylation of transcription factors and histone. The joint approach of immunology and engineering will help further develop the field of energy metabolite-based control of DC function, which has exciting potential for the discovery of new drug targets and development of therapeutics that treat an array of immune system-associated diseases.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.

保护我们人体免受疾病和疾病的免疫细胞需要发挥作用。能量途径可以通过递送代谢物（代谢涉及的物质）来操纵，从而可以改变免疫细胞功能和代谢。该职业项目将利用新的合成技术来生成代谢产物的纳米颗粒，然后将这些代谢产物传递到称为树突状细胞的专用免疫细胞，这对于初次免疫恢复的核心至关重要。这项工作将提高人们对免疫细胞中能量代谢产物介导的变化的了解，然后可以利用这些变化，以对包括感染，癌症和炎症性疾病在内的多种疾病产生强大的免疫反应。此外，在这个项目下，将设计电脑游戏，以教育玩家关于新陈代谢的各个方面。该项目还将吸引本科生和研究生，并将强调生物材料，代谢和免疫系统对周围公共社区的重要性。能源代谢是所有已知疾病和疾病的关键参与者（例如，癌症和自身免疫性疾病）；然而，对能量代谢物介导的免疫细胞的变化（例如转录因子和组蛋白糖基化/琥珀酰化）的理解不足。研究者的长期研究目标是研究基于代谢物的生物材料如何在表观遗传和功能水平上控制免疫细胞的功能。为了实现这一目标，该职业项目的重点是了解树突状细胞（DC）中能量代谢物，转录因子和功能蛋白轴。该研究提出了一种工程颗粒的方法，该方法在体外和体内为DC提供代谢物。该项目将通过开发基于代谢物的纳米颗粒的合成路线来做出工程贡献，这些纳米颗粒既可以用作载体和货物。生命科学贡献将通过确定DC中的代谢产物，转录因子和表观遗传标记之间的相关性来做出。重要的是，由于转录因子和组蛋白的琥珀酸化/糖基化，该项目将确定DCS的表观遗传变化。免疫学和工程的联合方法将有助于进一步发展基于能量代谢物的直流功能的控制领域，该领域具有令人兴奋的潜力，可以在发现新药物目标和理论的发展方面具有令人兴奋的潜力，这些疾病将一系列免疫学系统相关疾病。该奖项反映了NSF的法定任务，反映了通过基金会的智力评估来评估的支持，并通过评估了基础的智力。