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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的慢性移植物抗宿主病（cGVHD）已成为发病率和死亡率的主要原因之一异基因造血细胞移植（HCT）后，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，但通常无法成功预防。永久性器官损伤并与显着的脂肪酸（FA）代谢相关。然而，中链脂肪酸（MCFA）如何决定 T 细胞（Tc）的命运和功能。 GPR84 参与 cGVHD 病理学尚未被研究，作为 MCFA 传感。使用 cGVHD 患者和小鼠的外周血非核细胞 (PBMC) 和粪便。 cGVHD 模型中，我们阐明了 GPR84 信号在 cGVHD 病理学中的意义。当前研究计划的前提是了解 GPR84 介导的 MCFA 信号如何调节 T 细胞从而验证 GPR84 靶向是控制 cGVHD 的有效方法。目标 1，我们将阐明 GPR84 介导的 MCFA 代谢在 cGVHD 中的生物学功能。使用 GPR84 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。负责 GPR84 介导的 MCFA 信号传导在 cGVHD 病理学中的影响。同位素解析代谢组学、高维流式细胞术和单细胞 ATAC-seq，我们将验证如何 GPR84 信号通过调节细胞代谢来影响 Tc 和滤泡辅助 Tc (TFH) 的存活，我们将阐明已发现的 CD8+T 滤泡细胞 (TFC) 的功能。富含 cGVHD 患者的 PBMC，并阐明 GPR84 信号如何在治疗后调节这种新的细胞亚群在目标 3 中，我们研究 GPR84 靶向是否可以作为 cGVHD 的治疗选择。同时保留GVL效应，我们将使用药物拮抗剂的组合；诱导基因沉默和饮食编程方法与人对小鼠 cGVHD 模型来测试我们的我们还将研究 GPR84 靶向治疗是否能有效预防类固醇难治性疾病。因为 GPR84 抑制剂 GLPG1205 在 2 期临床试验中已被证明是安全有效的。饮食和微生物组调节疗法对于治疗 cGVHD 很重要，目前的研究该提案具有高度转化性且至关重要。