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: 10404145
• 负责人: Stephen Y Chan
• 金额: $ 30.64万
• 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/10404145
• 关键词: 18F-Glutamine; Automobile Driving; Bioenergetics; Biological Markers; Blood Platelets; Blood Vessels; Cells; Clinical; Clinical Research; Coculture Techniques; Collagen; 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; Modeling; 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; Sum; Symptoms; System; Systemic Scleroderma; Testing; Tracer; Transcription Coactivator; Vascular Proliferation; Vascular remodeling; Work; X-Ray Computed Tomography; biobank; cell type; clinical diagnostics; 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 Our unpublished data demonstrate that platelets from SSc patients show dysregulated mitochondrial energetics which correlate with the severity of vascular manifestations in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）是一种与全身性硬化症有关的致命疾病（SSC-PAH） 并取决于几种血管细胞类型。但是，分子串扰的关键系统仍然存在 神秘。以前，我们定义了转录共激活器yap/taz之间的关键调节轴 酶谷氨酰胺酶，建立了谷氨酰胺代谢如何相关的新范式 PAH的僵硬。但是，仍然存在关键问题。激活YAP/TAZ以启动PAH的触发器和 它们起源于单独的单元格类型吗？这些触发因素的下游，可以血管谷氨酰胺代谢 用作SSC-PAH的诊断指标？我们未发表的数据表明SSC患者的血小板 显示非调节的线粒体能量学，与这些血管表现的严重程度相关 患者并导致肺部外膜成纤维细胞的谷氨酰胺溶解增加。假设：变化的血小板 能量学信号向PA成纤维细胞，导致谷氨酰胺代谢的特定改变以对照 胶原蛋白沉积，血管刚度和SSC-PAH。在这项翻译建议中，我们将定义 SSC-PAH中血小板能量和成纤维细胞代谢的失调和成纤维细胞的存在。我们也会 确定是否可以将成纤维细胞谷氨酰胺摄取用于开发更有效的诊断。目的 1）确定血小板能量失调是否与血管的严重程度有关 SSC的症状以及SSC-PAH中的肺血管成纤维细胞谷氨酰胺溶解。我们假设 功能失调的血小板能量可以用作SSC进行性血管损伤的生物标志物，IS 与SSC-PAH中肺部外胞纤维细胞中谷氨酰胺溶解的增加有关。调查， 血小板将从SSC-PAH，SSC和对照患者中分离出来，并将分析能量特征，并将其能量分析。 与临床血管测量的测量相关。同时，人类SSC-的单细胞RNA测序 PAH与控制外植体肺将确定血小板能量转录谱是否与血管相关 成纤维细胞谷氨酰胺分析。目标2）利用18F-氟谷氨酰胺宠物成像来测量谷氨酰胺 SSC-PAH与控件的吸收。我们发现增加谷氨酰胺吸收到肺部血管和右 啮齿动物PAH中的心室，通过18F-FGLN示踪剂的PET成像和光谱（MIMS）成像来量化 15N-谷氨酰胺。在一项人口研究中，我们将研究SSC-PAH患者与SSC的18F-FGLN PET/CT 和未解决的控件。这个目标将定义谷氨酰胺代谢在人类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 团队的独特位置可以定义血小板到纤维细胞代谢途径关键的临床相关性 用于诱导血管僵硬和PAH。我们将利用这些发现进行首个人类诊断 研究18F-FGLN PET/CT的研究。总而言之，我们将定义在血小板和成纤维细胞上收敛的细胞间轴 SSC-PAH的代谢，因此在这种致命疾病中提供了急需的靶向诊断。