Exploring metabolic governance of immune cell form and function

探索免疫细胞形式和功能的代谢调控

• 批准号: 10725429
• 负责人: Daniel Puleston
• 金额: $ 49.46万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-08 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725429
• 关键词: Address; Adoptive Transfer; Adult; Alveolar; Biochemistry; Biology; Bone Marrow; Cardiac; Cell physiology; Cells; Cellular biology; Chimera organism; Circulation; Colony-Stimulating Factor Receptors; Development; Disease; Electric Conductivity; Embryo; Embryonic Development; Environment; Enzymes; Excision; GATA6 transcription factor; Generations; Genetic; Genetic Transcription; Growth Factor; Health; Homeostasis; Human; Human Activities; Immune; In Situ; In Vitro; Infusion procedures; Knock-out; Lesion; Liver; Longevity; Macrophage; Maintenance; Malignant neoplasm of ovary; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Organ; Orthoptics; Parabiosis; Pathogenicity; Pathway interactions; Patients; Perfusion; Peritoneum; Phenotype; Play; Polyamines; Primary carcinoma of the liver cells; Proxy; Pulmonary Surfactants; Role; Route; Shapes; Signal Transduction; System; Technology; Testing; Therapeutic; Tissue Model; Tissues; Tracer; Tumor-associated macrophages; cell type; human tissue; hypusine; immunoregulation; implantation; in vitro Assay; in vivo; innovation; metabolomics; monocyte; mouse model; mutant; neoplastic cell; novel; novel strategies; pathogen; pharmacologic; programs; self-renewal; tumor; tumor microenvironment; validation studies; virtual

PROJECT SUMMARY In this proposal we want to understand the metabolic factors that are essential to tissue-resident macrophage (TRM) development and function. New advances in metabolomics technology have helped to decode how cellular metabolism helps to shape immune cell form and function, but these developments have so far generally stopped short of meaningfully probing the metabolism of immune cells within the tissues themselves. For cells like TRMs, that exclusively reside within the tissues, a full understanding the biology of these cells is missing until we can identify how they utilize cellular metabolism to support their tissue-specific identity and function. Given the important roles TRMs play in maintaining tissue homeostasis and shaping pathogenic environments, it is essential we begin to probe the biochemistry of these cells. We present an approach for exploring TRM metabolism in vivo. Through the use of metabolic tracers in vivo and rapid isolation of TRMs from the tissue, we detail how this approach will be used to identify metabolic programs essential to TRM development and function within the tissues. We show how proof of principle testing of this framework reveals the polyamine-hypusine axis as a novel metabolic node active in differentiating monocytes and TRMs. We implement in vitro and in vivo validation studies laid out in our framework, which include bone marrow chimera, parabiosis and novel mouse model creation, to show that this pathway is essential for the development and maintenance of TRMs across a multitude of organs. We also propose a highly novel approach to studying TRM metabolism in humans. Using normathemic perfusion machines, we will perfuse human organs with metabolic tracers to gain an understanding of human TRM biology in situ. Crucially, we will employ this approach to experimentally test the pathways identified as important in mouse TRMs in a human setting. Finally, a major focus of this proposal is to explore TRM metabolism within tumors. Using similar approaches outlined above for TRMs during homeostasis, we will evaluate the metabolic activity of TAMs using well defined murine tumor models. We will use our innovative human system that allows us to experimentally manipulate human organs to probe the metabolism of human hepatocellular carcinoma lesions and of the TRMs that reside inside them. Through these orthogonal approaches across species, we expect to build up a detailed picture of tumor macrophage metabolic activity that can be used to identify novel pathways that can be targeted to modulate these cells within tumors for therapeutic benefit.

项目摘要 在这个建议中，我们想了解的代谢因素是必不可少的组织驻留 巨噬细胞（TRM）的发育和功能。代谢组学技术的新进展 有助于解码细胞代谢如何帮助塑造免疫细胞的形式和功能， 到目前为止，这些进展一般都没有对新陈代谢进行有意义的探索， 免疫细胞在组织中的作用。对于像TRM这样的细胞，它们只存在于 在我们能够确定这些细胞是如何在体内生长的之前， 利用细胞代谢来支持其组织特异性身份和功能。鉴于重要的 TRM在维持组织稳态和塑造致病环境中发挥作用， 我们必须开始探索这些细胞的生物化学。我们提出了一种方法来探索 体内TRM代谢。通过使用体内代谢示踪剂和快速分离TRM 从组织中，我们详细介绍了这种方法将如何用于确定代谢程序的基本 TRM在组织内的发育和功能。我们展示了如何证明的原则测试 该框架揭示了多胺-羟腐胺赖氨酸轴作为一种新的代谢节点， 区分单核细胞和TRM。我们实施体外和体内验证研究， 在我们框架中，包括骨髓嵌合体、联体共生和新型小鼠模型 创造，以表明这一途径是必不可少的发展和维护的TRM 在许多器官上。我们还提出了一个非常新颖的方法来研究TRM 人体的新陈代谢使用降血压灌注机，我们将灌注人体器官 与代谢示踪剂，以获得了解人类TRM生物学原位。最重要的是， 采用这种方法来实验性地测试在小鼠TRM中被识别为重要的途径 在人类的环境中。最后，本提案的一个主要重点是探索TRM代谢， 肿瘤的使用类似的方法，上述TRM在稳态，我们将评估 使用明确定义的鼠肿瘤模型的TAM的代谢活性。我们将利用我们的创新 人类系统，允许我们实验性地操纵人体器官， 人肝细胞癌病变和驻留在其中的TRM的代谢。 通过这些跨物种的正交方法，我们希望建立一个详细的图片， 肿瘤巨噬细胞代谢活性，可用于确定新的途径， 靶向调节肿瘤内的这些细胞以获得治疗益处。