CD38 modulation of NAD metabolism driving scleroderma pathogenesis

CD38 调节 NAD 代谢驱动硬皮病发病机制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要在系统性硬化症（SSC）中，纤维化会在多个器官中造成永久性功能损害。尽管 SSC中的非分辨纤维化具有致命的后果，其机制知之甚少，没有有效的治疗。根据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，即纤维化结果从烟酰胺腺嘌呤二核苷酸（NAD）和烟酰胺（NAM）代谢的失调。通过酶CD38（将NAD分解为NAM）和烟酰胺N-甲基转移酶（NNMT），它们夫妻的细胞代谢状态与甲基化体的变化和细胞重编程。而且，我们建议该多细胞CD38-NNMT代谢轴代表了SSC治疗的新靶标。我们的初步结果表明1）在SSC患者活检中，CD38和NNMT的表达升高，这两个NAD- 代谢酶主要映射为免疫（CD38）或基质（NNMT）细胞； 2）小鼠中CD38的遗传或药理阻滞受到保护免受纤维化的保护； 3）NAM，主要酶促通过CD38生成燃料活性的NNMT的底物； 4）NNMT是TGF-ß诱导的，它的抑制作用消除了纤维化反应。我们的小说范式建立在这些观察之上，牵涉到 SSC发病机理中通过CD38和NNMT介导的NAD代谢失调。具体来说，我们提高SSC中CD38活性升高的提议会减少NAD，同时生成NAM，然后才能驱动成纤维细胞通过加油NNMT活性和其他机制进行重编程。这种代谢相互作用表达CD38和表达NNMT的细胞可能被选择性地靶向纤维化治疗。尽管我们引人入胜的观察，NAD代谢酶CD38和NNMT的改变及其 SSC代谢细胞网络中的致病作用，细胞来源和相互相互作用从未因此，我们将使用综合实验策略部署患者样本，新型工程小鼠和疾病模型以及药理剂。在AIM 1中，我们将在SSC患者中绘制CD38的表达并确定CD38的细胞特定于纤维化的特定角色和机制。在AIM 2中，我们将在SSC患者活检中绘制NNMT的表达并确定其细胞类型特异性的致病作用，机制和与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 NNMT在SSC中的NAD NAD代谢失调，我们将产生基本的机理理解以指导发现全新的治疗方法，以减少SSC的严重性或延迟其致命发作并发症。