A platelet-fibroblast axis connecting bioenergetics and metabolism in SSc-pulmonary arterial hypertension

连接 SSc 肺动脉高压生物能学和代谢的血小板-成纤维细胞轴

• 批准号: 10705673
• 负责人: Stephen Y Chan
• 金额: $ 30.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705673
• 关键词: 18F-Glutamine; Automobile Driving; Bioenergetics; Biological Markers; Blood Platelets; Blood Vessels; Cells; Clinical; Clinical Research; Coculture Techniques; Collagen; Communication; Critical Pathways; Data; Deposition; Detection; Development; Diagnostic; Disease; Enzymes; Fatty Acids; Feedback; Fibroblasts; Functional disorder; Gene Expression Profile; Glucose; Glutaminase; Glutamine; Human; Image; Imaging Techniques; Link; Lung; Maintenance; Measures; Mediating; Metabolism; Mitochondria; Molecular; Oxidative Phosphorylation; PET/CT scan; Pathogenicity; Patients; Persons; Positioning Attribute; Positron-Emission Tomography; Pulmonary vessels; Right ventricular structure; Rodent; Role; Severities; Shapes; Signal Transduction; Skin; Symptoms; System; Systemic Scleroderma; Testing; Tracer; Transcription Coactivator; Vascular Proliferation; Vascular remodeling; Work; X-Ray Computed Tomography; biobank; cell type; clinical diagnostics; clinical translation; clinically relevant; early detection biomarkers; first-in-human; human RNA sequencing; human study; innovation; multidisciplinary; novel; novel diagnostics; oxidation; pulmonary arterial hypertension; single-cell RNA sequencing; translational study; uptake

Pulmonary arterial hypertension (PAH) is a deadly disease associated with systemic sclerosis (SSc-PAH) and is dependent on several vascular cell types. However, key systems of molecular cross-talk remain enigmatic. Previously, we defined a key regulatory axis between the transcriptional coactivators YAP/TAZ with the enzyme glutaminase, establishing a new paradigm of how glutamine metabolism is related to vascular stiffness in PAH. Yet, crucial questions remain. What are the triggers that activate YAP/TAZ to initiate PAH and do they originate from separate cell types? Downstream of those triggers, can vascular glutamine metabolism serve as a diagnostic indicator of SSc-PAH? Our unpublished data demonstrate that platelets from SSc patients show dysregulated mitochondrial energetics which correlate with the severity of vascular manifestations in these patients and cause increased glutaminolysis in pulmonary adventitial fibroblasts. Hypothesis: Altered platelet energetics signal to PA fibroblasts, resulting in specific alterations of glutamine metabolism to control collagen deposition, vascular stiffness, and SSc-PAH. In this translational proposal, we will define the presence of dysregulated platelet energetics and fibroblast glutamine metabolism in SSc-PAH. We will also determine if fibroblast glutamine uptake can be targeted for the development of more effective diagnostics. Aim 1) Determine whether dysregulated platelet energetics is associated with the severity of vascular symptoms in SSc and with lung vascular fibroblast glutaminolysis in SSc-PAH. We postulate that dysfunctional platelet energetics can serve as a biomarker of progressive vascular damage in SSc and is associated with increased glutaminolysis in pulmonary adventitial fibroblasts in SSc-PAH. To investigate, platelets will be isolated from SSc-PAH, SSc, and control patients and energetic profiles will be analyzed and correlated with measures of clinical vascular measures. In parallel, single cell RNA sequencing of human SSc- PAH vs. control explant lungs will determine if platelet energetic transcriptional profiles correlate with vascular fibroblast glutaminolytic profiles. Aim 2) Utilize 18F-fluoroglutamine PET imaging to measure glutamine uptake in SSc-PAH vs. controls. We found increased glutamine uptake into pulmonary vessels and right ventricle in rodent PAH, as quantified by PET imaging of a 18F-FGln tracer and by spectral (MIMS) imaging of 15N-glutamine. In a first-in-human study, we will investigate 18F-FGln PET/CT in SSc-PAH patients vs. SSc alone and non-diseased controls. This aim will define the relevance of glutamine metabolism in human SSc-PAH and the potential of 18F-FGln to serve as a novel diagnostic tracer for SSc-PAH. Significance: Our multi-disciplinary team is uniquely positioned to define the clinical relevance of a platelet-to-fibroblast metabolism pathway critical for inducing vascular stiffening and PAH. We will leverage those findings to embark on a first-in-human diagnostic study of 18F-FGln PET/CT. In sum, we will define the intercellular axes that converge upon platelet and fibroblast metabolism in SSc-PAH, thus offering much needed targeted diagnostics in this deadly disease.

肺动脉高压（PAH）是一种与系统性硬化症（SSc-PAH）相关的致命疾病 并且依赖于几种血管细胞类型。然而，关键系统的分子串扰仍然存在 神秘莫测以前，我们定义了转录辅激活因子雅普/TAZ之间的关键调控轴， 谷氨酰胺酶，建立了谷氨酰胺代谢如何与血管相关的新范例， PAH的硬度。然而，关键问题依然存在。激活雅普/TAZ以引发PAH和 它们是否来自不同的细胞类型？在这些触发器的下游，血管谷氨酰胺代谢 作为SSc-PAH的诊断指标？我们未发表的数据表明，SSc患者的血小板 显示线粒体能量失调，与这些患者血管表现的严重程度相关。 患者，并导致肺外膜成纤维细胞中的精氨酸溶解增加。假设：血小板改变 能量信号PA成纤维细胞，导致谷氨酰胺代谢的特定改变，以控制 胶原沉积、血管僵硬和SSc-PAH。在这个翻译建议中，我们将定义 SSc-PAH中存在血小板能量学和成纤维细胞谷氨酰胺代谢失调。我们还将 确定成纤维细胞谷氨酰胺摄取是否可以作为开发更有效诊断的目标。目的 1)确定血小板能量学失调是否与血管性心力衰竭的严重程度相关。 SSc中的症状和SSc-PAH中的肺血管成纤维细胞氨溶解。我们推测 功能障碍的血小板能量学可以作为SSc中进行性血管损伤的生物标志物， 与SSc-PAH中肺外膜成纤维细胞中的多巴胺溶解增加相关。为了调查， 将从SSc-PAH、SSc和对照患者中分离血小板，并分析能量分布， 与临床血管测量指标相关。平行地，人SSc的单细胞RNA测序- PAH与对照外植体肺将确定血小板能量转录谱是否与血管生成相关。 成纤维细胞溶氨谱。目的2）利用18F-氟代谷氨酰胺PET显像测定谷氨酰胺 与对照相比，SSc-PAH的摄取。我们发现谷氨酰胺摄取增加到肺血管和右 通过18F-FGln示踪剂的PET成像和18F-FGln示踪剂的光谱（MIMS）成像定量， 15 N-谷氨酰胺。在一项首次人体研究中，我们将研究SSc-PAH患者与单纯SSc患者的18F-FGln PET/CT 和未患病的对照。这一目标将确定谷氨酰胺代谢在人SSc-PAH和 18F-FGln作为SSc-PAH的新型诊断示踪剂的潜力。意义：我们的多学科 该团队具有独特的优势，可以确定血小板-成纤维细胞代谢途径的临床相关性， 导致血管硬化和PAH我们将利用这些发现着手进行首次人体诊断 18F-FGln PET/CT研究总之，我们将定义聚集在血小板和成纤维细胞上的细胞间轴 因此，在这种致命疾病中提供急需的靶向诊断。