Novel mechanism for eNAMPT secretion in PAH vascular remodeling

PAH 血管重塑中 eNAMPT 分泌的新机制

• 批准号: 10677318
• 负责人: Marisela Rodriguez
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-24 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677318
• 关键词: ATP-Binding Cassette Transporters; Acute Respiratory Distress Syndrome; Address; Antioxidants; Apoptosis; Binding; Blood Vessels; Cell Proliferation; Cell Separation; Cell Survival; Cell membrane; Cells; Cessation of life; Dimerization; Disease; Endothelial Cells; Endothelin-1; Endothelium; Enzymes; Epithelium; Functional disorder; Generations; Genetic Transcription; Genomics; Human; Hypertrophy; Hypoxia; Inflammasome; Inflammatory; Inflammatory Response; Laboratories; Leukocytes; Ligation; Luciferases; Lung; Lymphocyte; Medial; Mesenchymal; Molecular; Natural Immunity; Nicotinamide adenine dinucleotide; Pathway interactions; Patients; Pattern; Plasma; Platelet-Derived Growth Factor; Predisposition; Process; Procollagen-Proline Dioxygenase; Progressive Disease; Proliferating; Proteins; Pulmonary Circulation; Pulmonary Fibrosis; Pulmonary Vascular Resistance; Pulmonary artery structure; Reporter; Resistance; Response Elements; Right Ventricular Dysfunction; Right Ventricular Function; Rodent; Role; Severities; Signal Transduction; Smooth Muscle Myocytes; Stimulus; TLR4 gene; Tertiary Protein Structure; Therapeutic; Tissues; Training; Transcriptional Regulation; Translations; Vascular Endothelial Growth Factors; Vascular remodeling; curative treatments; cytokine; extracellular; extracellular vesicles; improved; inhibitor; insight; mutant; neutralizing monoclonal antibodies; nicotinamide phosphoribosyltransferase; novel; pharmacologic; pre-clinical; promoter; pulmonary arterial hypertension; pulmonary arterial pressure; pulmonary vascular remodeling; response; right ventricular failure; therapeutic target; transcription factor

ABSTRACT Pulmonary arterial hypertension (PH) is a progressive disease leading to pulmonary vascular remodeling, increased pulmonary arterial pressures, declining right ventricular (RV) function, right heart failure, and death. No curative therapies are currently available. In this F31 application, the PI will train in the acclaimed translational laboratory of Joe GN Garcia, MD and seek to address the unmet need for novel effective PAH therapeutic strategies by focusing on eNAMPT (extracellular nicotinamide phosphoribosyltransferase). eNAMPT is a novel damage-associated molecular pattern protein (DAMP) and PAH target identified by the Garcia lab utilizing genomic–intensive approaches. Intracellular NAMPT mainly serves as a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) synthesis. However, secreted extracellular eNAMPT (from leukocytes, lymphocytes, endothelium, epithelium) ligates the Toll-like receptor 4 (TLR4) to potently activate this inflammatory signaling cascade. eNAMPT/TLR4 participation in innate immunity inflammatory responses is key to the severity of several serious inflammatory disorders (ARDS, lung fibrosis) including PH with elevated plasma eNAMPT levels in PH subjects correlating with RV dysfunction. Increased eNAMPT secretion is influenced by NAMPT promoter SNPs and NAMPT transcriptional regulation by anti-oxidant response elements and hypoxia response elements induced by transcription factors such as HIF-2α. We have demonstrated that the eNAMPT/TLR4 pathway is highly druggable as a humanized eNAMPT-neutralizing mAb effectively reduced the severity of preclinical PH. Several key gaps remain, however, in fundamentally understanding the role of eNAMPT in PH pathobiology. For example, it remains unclear as to whether endothelial cells (ECs) or smooth muscle cells (SMCs) are the primary target cell for eNAMPT involvement in PH. In Specific Aim #1 (SA), the PI will examine EC- and SMC-specific NAMPT promoter responses to PAH stimuli that increase NAMPT transcriptional activities and translation. SA #2 will investigate the EC- and SMC-specific intracellular mechanisms contributing to eNAMPT secretion into the circulation by PAH stimuli focusing on the role of NAMPT dimerization, inflammasome and ABC transporter activation and generation of extracellular vesicles. Finally, utilizing human and rodent tissues, SA #3 will define EC- and SMC-specific eNAMPT-induced responses by examining cytosolic Ca2+ signaling, cell proliferation/activation, cell survival, EMT activity and angiogenic activity as readouts. Together, these studies will provide key novel mechanistic insights into eNAMPT’s influence on vascular remodeling and PH pathobiology.

摘要