Targeting medium chain fatty acid metabolism for the treatment of chronic Graft-versus-Host Disease

靶向中链脂肪酸代谢治疗慢性移植物抗宿主病

• 批准号: 10567013
• 负责人: Hung Nguyen
• 金额: $ 58.27万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567013
• 关键词: ATAC-seq; Adrenal Cortex Hormones; Affect; Allogenic; B-Cell Activation; B-Lymphocytes; Biological Assay; Biological Process; Biology; Bronchiolitis Obliterans; CD8B1 gene; CRISPR/Cas technology; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Clinical; Data; Development; Diet; Disease model; Epigenetic Process; Fatty Acids; Fibrosis; Flow Cytometry; Functional disorder; GPR84 gene; Gene Silencing; Genetic; Glucose; Glutamine; Glycolysis; Goals; Graft-Versus-Tumor Induction; Helper-Inducer T-Lymphocyte; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Human; Immune; In Vitro; Inflammation; Isoantibodies; Knock-out; Knockout Mice; Mediating; Medium chain fatty acid; Metabolic; Metabolism; Mitochondria; Morbidity - disease rate; Mus; Organ; Oxidative Phosphorylation; Pathogenicity; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Phenotype; Prevention; Proliferating; Refractory; Research Proposals; Resources; Role; Sampling; Scleroderma; Signal Transduction; Steroids; Structure of germinal center of lymph node; System; T cell differentiation; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tissues; Toxic effect; Tracer; Transplant Recipients; Volatile Fatty Acids; antagonist; chronic graft versus host disease; curative treatments; dietary; disorder prevention; effective therapy; efficacy testing; experimental study; fatty acid metabolism; glucose uptake; graft vs leukemia effect; gut microbiome; hematopoietic cell transplantation; high dimensionality; improved; inhibitor; long chain fatty acid; metabolic fitness; metabolomics; microbiome; migration; mitochondrial fitness; mortality; mouse model; novel; novel therapeutics; peripheral blood; pharmacologic; post-transplant; preservation; prevent; receptor; research study; stable isotope; transcriptome sequencing; tumor

Abstract Chronic graft versus host disease (cGVHD) has emerged as one of the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). However, there is limited therapeutic option for cGVHD prevention and therapy. Steroid, the standard initial therapy of cGVHD, often is unsuccessful in preventing permanent organs damage and has been associated with significant toxicities. Fatty acid (FA) metabolism decides T cell (Tc) fate and function in cGVHD development. However, how medium chain fatty acid (MCFA) participates in cGVHD pathobiology has not been studied. GPR84 has been well known as the MCFA sensing receptor. Using peripheral blood nonnuclear cells (PBMCs) and fecals from cGVHD patients along with murine models of cGVHD, we elucidate the implication of GPR84 signaling in cGVHD pathobiology. The scientific premise of current research proposal is to understand how GPR84- mediated MCFA signaling regulates T cell metabolism in cGVHD and therefore validate GPR84 targeting as an effective approach to control cGVHD. In Aim 1, we will elucidate the biological function of GPR84-mediated MCFA metabolism in cGVHD. We will use GPR84 genetically knockout mice and MCFA- enriched diet to understand the role of MCFA signaling in bronchiolitis obliterans (BO)-, and thymus-damaged cGVHD. In Aim 2, we will elucidate mechanisms responsible for the impact of GPR84- mediated MCFA signaling in cGVHD pathobiology. Utilizing stable isotope-resolved metabolomics, high dimensional flow cytometry, and single cell ATAC-seq, we will validate how GPR84 signaling by regulating cellular metabolism would influence Tc and follicular helper Tc (TFH) survival, migration, differentiation, and function. We will elucidate the function CD8+T follicular cells (TFC), which is found enriched in cGVHD patient’s PBMCs and elucidate how GPR84 signaling regulates this novel cell subset post- transplant. In Aim 3, we investigate whether GPR84 targeting would be a therapeutic option for cGVHD while preserving the GVL effect. We will use a combination of pharmacological antagonist; CRISPR-cas9 induced gene silencing, and diet programming approaches with human-to-mouse cGVHD model to test our hypothesis. We will also examine if GPR84 targeting would be effective in the prevention steroid refractory cGVHD. Because GPR84 inhibitor GLPG1205 has been found safe and effective in phase 2 clinical; precise dietaries and microbiome- modulating therapies are important in the treatment of cGVHD, current research proposal is highly translational and critically important.

摘要 慢性移植物抗宿主病（cGVHD）已成为导致发病和死亡的主要原因之一 异基因造血细胞移植（HCT）后。然而，cGVHD的治疗选择有限 预防和治疗。类固醇是cGVHD的标准初始治疗， 永久性器官损伤，并与显著毒性相关。脂肪酸（FA）代谢 决定T细胞（Tc）在cGVHD发展中的命运和功能。中链脂肪酸（MCFA） 参与cGVHD病理生物学尚未研究。GPR 84被称为MCFA传感器， 受体的使用来自cGVHD患者的外周血非核细胞（PBMC）和粪便沿着小鼠 cGVHD模型，我们阐明了GPR 84信号转导在cGVHD病理生物学中的意义。科学 目前研究的前提是了解GPR 84介导的MCFA信号如何调节T细胞 因此，本发明的目的是为了验证GPR 84靶向作为控制cGVHD的有效方法。在 目的1：阐明GPR 84介导的MCFA代谢在cGVHD中的生物学功能。我们将 使用GPR 84基因敲除小鼠和富含MCFA的饮食来了解MCFA信号传导在 闭塞性细支气管炎（BO）-和胸腺损伤的cGVHD。在目标2中，我们将阐明机制 在cGVHD病理生物学中负责GPR 84介导的MCFA信号传导的影响。利用稳定 同位素分辨代谢组学，高维流式细胞术和单细胞ATAC-seq，我们将验证如何 GPR 84信号通过调节细胞代谢影响Tc和卵泡辅助Tc（TFH）存活， 迁移、分化和功能。我们将阐明CD 8 +T滤泡细胞（TFC）的功能，这是发现 在cGVHD患者的PBMC中富集，并阐明GPR 84信号转导如何调节这种新的细胞亚群， 移植在目标3中，我们研究GPR 84靶向是否是cGVHD的治疗选择。 同时保持GVL效应。我们将使用药理学拮抗剂的组合; CRISPR-cas9 诱导的基因沉默，和饮食编程方法与人-小鼠cGVHD模型，以测试我们的 假说.我们还将研究GPR 84靶向是否能有效预防类固醇难治性 cGVHD。由于GPR 84抑制剂GLPG 1205在II期临床中被发现安全有效;精确 当前研究表明，饮食和微生物组调节疗法对于治疗cGVHD非常重要 该提案具有高度的翻译性和至关重要的意义。