CD38 modulation of NAD metabolism driving scleroderma pathogenesis

CD38 调节 NAD 代谢驱动硬皮病发病机制

• 批准号: 10733929
• 负责人: Eduardo N Chini
• 金额: $ 68.27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733929
• 关键词: Ablation; Address; Animal Model; Automobile Driving; Biopsy; Bleomycin; Blocking Antibodies; Cells; Chronic Disease; Complex; Computer Analysis; Confocal Microscopy; Consumption; Couples; Coupling; Cutaneous sclerosis; Development; Disease; Disease model; Engineering; Enzymes; Epigenetic Process; Event; Fibroblasts; Fibrosis; Genetic; Homeostasis; Immune; In Vitro; Infiltration; Knockout Mice; Laboratories; Link; LoxP-flanked allele; Lung; Maps; Mediating; Metabolic; Metabolism; Methylation; Modeling; Mus; Myofibroblast; NAD+ Nucleosidase; Niacinamide; Nicotinamide N-Methyltransferase; Nicotinamide adenine dinucleotide; Organ; Organ Model; Pathogenesis; Pathogenicity; Pathologic; Patients; Phenotype; Play; Process; Pulmonary Fibrosis; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Sampling; Scheme; Scleroderma; Severities; Skin; Source; Stromal Cells; Systemic Scleroderma; Tissues; Transferase; Transforming Growth Factor beta; Up-Regulation; cell type; chromatin remodeling; effective therapy; guided inquiry; human subject; in vivo; indium-bleomycin; innovation; insight; methylome; mouse model; novel; novel strategies; novel therapeutic intervention; pharmacologic; prevent; public health relevance; response; single-cell RNA sequencing; skin fibrosis; targeted treatment

PROJECT SUMMARY/ABSTRACT In systemic sclerosis (SSc), fibrosis causes permanent functional damage in multiple organs. While non-resolving fibrosis in SSc has lethal consequences, its mechanisms are poorly understood and there is no effective treatment. Based on our exciting findings, we now propose the very novel hypothesis that fibrosis results from dysregulation of nicotinamide adenine dinucleotide (NAD) and nicotinamide (NAM) metabolism mediated by the enzymes CD38 (which breaks down NAD to NAM), and nicotinamide N-methyltransferase (NNMT), which couples cellular metabolic states to methylome changes and cellular reprogramming. Moreover, we propose that this multicellular CD38-NNMT metabolic axis represents a novel target for SSc therapy. Our preliminary results show that 1) expression of CD38 and NNMT are elevated in SSc patient biopsies, with these two NAD- metabolizing enzymes mapping predominantly to immune (CD38) or stromal (NNMT) cells, respectively; 2) genetic or pharmacological blockade of CD38 in mice is protective from fibrosis; 3) NAM, the main enzymatic substrate of NNMT that fuels its activity, is generated via CD38; and 4) NNMT is TGF-ß-inducible, and its inhibition abrogates fibrotic responses. Our novel paradigm, built upon these observations, implicates dysregulated NAD metabolism mediated via CD38 and NNMT in the pathogenesis of SSc. Specifically, we propose that elevated CD38 activity in SSc reduces NAD while generating NAM, both of which then drive fibroblast reprogramming via fueling NNMT activity and other mechanisms. This metabolic interplay between CD38-expressing and NNMT-expressing cells might be selectively targeted for fibrosis treatment. Despite our compelling observations, alterations in the key NAD metabolizing enzymes CD38 and NNMT, and their pathogenic roles, cellular sources and reciprocal interaction in a metabolic cellular network in SSc have never been investigated. We will therefore address these critical gaps in this proposal using a comprehensive experimental strategy deploying patient samples, novel engineered mice and disease models and pharmacological agents. In Aim 1 we will map CD38 expression in SSc patients and determine CD38's cell type-specific roles and mechanisms in fibrosis. In Aim 2 we will map NNMT expression in SSc patient biopsies and determine its cell type-specific pathogenic roles, mechanisms and interplay with CD38. The premise of our highly innovative proposal is that by elucidating the pathogenic roles and mechanistic links between CD38 and NNMT underlying dysregulated NAD metabolism in SSc, we will generate fundamental mechanistic understanding to guide discovery of entirely new treatments to reduce severity of SSc or delay onset of its deadly complications.

项目概要/摘要 在系统性硬化症（SSc）中，纤维化会导致多个器官的永久性功能损伤。尽管 SSc 中的非解决性纤维化具有致命的后果，其机制知之甚少，并且没有 有效的治疗。基于我们令人兴奋的发现，我们现在提出了一个非常新颖的假设：纤维化导致 由烟酰胺腺嘌呤二核苷酸 (NAD) 和烟酰胺 (NAM) 代谢调节失调引起 通过酶 CD38（将 NAD 分解为 NAM）和烟酰胺 N-甲基转移酶 (NNMT)， 将细胞代谢状态与甲基化组变化和细胞重编程结合起来。此外，我们建议 这种多细胞 CD38-NNMT 代谢轴代表了 SSc 治疗的新靶点。我们的初步结果 显示 1) CD38 和 NNMT 的表达在 SSc 患者活检中升高，这两种 NAD- 主要分别映射到免疫（CD38）或基质（NNMT）细胞的代谢酶； 2） 对小鼠 CD38 进行遗传或药理学阻断可防止纤维化； 3）NAM，主要酶 促进其活性的 NNMT 底物是通过 CD38 产生的； 4) NNMT 是 TGF-β 诱导型，其 抑制消除纤维化反应。我们的新颖范式建立在这些观察的基础上，暗示 SSc 发病机制中通过 CD38 和 NNMT 介导的 NAD 代谢失调。具体来说，我们 提出 SSc 中 CD38 活性升高会减少 NAD，同时生成 NAM，然后两者都会驱动 通过促进 NNMT 活性和其他机制进行成纤维细胞重编程。这种代谢相互作用 表达 CD38 和表达 NNMT 的细胞可能是纤维化治疗的选择性靶点。尽管我们的 令人信服的观察结果，关键 NAD 代谢酶 CD38 和 NNMT 的改变及其作用 SSc 中代谢细胞网络的致病作用、细胞来源和相互相互作用从未 被调查。因此，我们将使用全面的方法来解决本提案中的这些关键差距 部署患者样本、新型工程小鼠和疾病模型的实验策略以及 药理制剂。在目标 1 中，我们将绘制 SSc 患者中 CD38 表达图谱并确定 CD38 细胞 纤维化中的类型特异性作用和机制。在目标 2 中，我们将绘制 SSc 患者活检中的 NNMT 表达图 并确定其细胞类型特异性致病作用、机制以及与 CD38 的相互作用。我们的前提 高度创新的建议是通过阐明CD38和CD38之间的致病作用和机制联系 NNMT 是 SSc 中 NAD 代谢失调的基础，我们将产生基本机制 了解指导发现全新的治疗方法，以减轻 SSc 的严重程度或延缓其致命性的发作 并发症。