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.

免疫细胞保护我们的身体免受疾病和紊乱的伤害，需要能量来发挥作用。能量途径可以通过代谢产物(参与新陈代谢的物质)的传递来操纵，代谢产物可以改变免疫细胞的功能和新陈代谢。这个职业项目将利用新的合成技术来产生代谢物的纳米颗粒，然后将这些代谢物输送到被称为树突状细胞的专门免疫细胞，树突状细胞是启动初级免疫反应的关键。这项工作将促进对能量代谢物介导的免疫细胞变化的理解，这些变化随后可以被用来产生针对各种疾病的强大免疫反应，包括感染、癌症和炎症性疾病。此外，在这个项目下，将设计一个电脑游戏来教育玩家新陈代谢的各个方面。这个项目还将吸引本科生和研究生参与，并将突出生物材料、新陈代谢和免疫系统对周围公共社区的重要性。能量新陈代谢是所有已知疾病和紊乱(例如癌症和自身免疫性疾病)的关键因素；然而，在表观遗传水平上对能量代谢物介导的免疫细胞变化(例如转录因子和组蛋白糖基化/琥珀酸化)知之甚少。研究人员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。朝着这一目标，这个职业项目的重点是了解树突状细胞(DC)中的能量代谢物、转录因子和功能蛋白轴。这项研究提出了一种在体外和体内将代谢物运送到DC的工程颗粒的方法。该项目将通过开发以代谢物为基础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作为载体，也可以作为货物。将通过确定DC中代谢物、转录因子和表观遗传标记之间的相关性来做出生命科学贡献。重要的是，这个项目将确定树突状细胞由于转录因子和组蛋白的琥珀酸化/糖基化而发生的表观遗传学变化。免疫学和工程学的联合方法将有助于进一步发展基于能量代谢产物的DC功能控制领域，这在发现新药靶点和开发治疗一系列免疫系统相关疾病的疗法方面具有令人兴奋的潜力。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。