Complement Mediated Remodeling in Pulmonary Vascular Disease

肺血管疾病中补体介导的重塑

• 批准号: 10686922
• 负责人: Kurt R. Stenmark
• 金额: $ 275.42万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686922
• 关键词: Address; Age; Animal Model; Animals; Automobile Driving; Biological Markers; Biological Models; Blood Platelets; Blood Vessels; Cattle; Cells; Cessation of life; Chimeric Proteins; Chronic; Clinical; Complement; Complement Activation; Development; Diagnosis; Disease; Disease Progression; Endothelium; Environment; Experimental Animal Model; Extracellular Matrix; Genetic Heterogeneity; Genetic Processes; Genetic Transcription; Goals; Heterogeneity; Human; Hypoxia; Image; Immunity; Immunoglobulins; Individual; Inflammation; Inflammatory; Intervention; Investigation; Lesion; Link; Lung; Macrophage; Mass Spectrum Analysis; Mediating; Methodology; Modeling; Molecular; Molecular Profiling; Monoclonal Antibodies; Morbidity - disease rate; Mouse Protein; Mus; Natural Immunity; Pathogenesis; Pathogenicity; Pathologic; Patients; Peptide Initiation Factors; Phenotype; Platelet Activation; Play; Positioning Attribute; Process; Proteome; Proteomics; Pulmonary Hypertension; Pulmonary arterial remodeling; Rattus; Research Personnel; Resolution; Role; SU 5416; Schistosoma; Schistosomiasis; Shapes; Signal Transduction; Site; T-Lymphocyte; Techniques; Testing; Thrombospondin 1; Tissues; Transplantation; United States Food and Drug Administration; Vascular remodeling; adaptive immunity; antibody detection; circulating biomarkers; complement pathway; disease heterogeneity; extracellular; hypoxia-induced pulmonary hypertension; in vivo; individualized medicine; inhibitor; lung vascular inflammation; monocyte; mortality; neoantigens; novel; novel therapeutics; pulmonary arterial hypertension; pulmonary vascular disorder; recruit; sex; translational goal; treatment response; vascular inflammation

Pulmonary arterial hypertension (PAH) afflicts patients of both sexes and across a broad age range and is highly lethal, if not promptly diagnosed and appropriately treated. Despite advances in the understanding of its pathogenesis and the development of 14 therapies approved by the United States Food and Drug Administration (FDA) over the past 2-3 decades, it continues to be associated with significant morbidity and mortality. The fundamental premise in this PPG is that PAH is highly heterogeneous regarding clinical parameters including initiating factors, clinical presentation, rate of progression, and response to therapy. Importantly, patient-to- patient heterogeneity, involving the types of pulmonary vascular lesions and the corresponding endotypes (i.e., underlying molecular processes driving the specific disease presentation), has been uncovered by our group and underlies the high complexity of disease pathogenesis. The paucity of investigations of these broader aspects of heterogeneity has resulted in a lack of understanding of specific factors contributing to particular sub- phenotypes of PAH – negatively impacting the development of more targeted (and individualized) therapies. These limitations manifest in the fact that some patients live many years on currently available treatments – however without cure of their disease -, while others progress rapidly and inexorably from onset to transplantation or death. This proposal seeks to uncover novel pathogenetic processes linking pulmonary vascular inflammation, remodeling, and molecular underpinnings of pulmonary vascular lesions in PH, while recognizing the key pathological and pathobiological heterogeneity of the disease. The central premise to be tested in this proposal is that early and persistent local, pulmonary vascular-specific activation of complement leads to persistent perivascular inflammation and extracellular matrix changes, thus shaping a feed-forward loop of pro- inflammatory/pro-remodeling perivascular microenvironment, leading to development of PH. This application represents a major step towards identifying new biomarkers and more effective individualized treatments, which are critically needed.

肺动脉高压（PAH）是一种不分性别、不分年龄的疾病

项目成果

Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection.

• DOI: 10.1165/rcmb.2022-0373oc
• 发表时间: 2023-08
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4

Hepatic-Specific Decrease in the Expression of Selenoenzymes and Factors Essential for Selenium Processing After Endotoxemia.

• DOI: 10.3389/fimmu.2020.595282
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Sherlock LG;Sjostrom K;Sian L;Delaney C;Tipple TE;Krebs NF;Nozik-Grayck E;Wright CJ
• 通讯作者: Wright CJ

Myoscaffolds reveal laminin scarring is detrimental for stem cell function while sarcospan induces compensatory fibrosis.

• DOI: 10.1038/s41536-023-00287-2
• 发表时间: 2023-03-15
• 期刊: NPJ REGENERATIVE MEDICINE
• 影响因子: 7.2
• 作者: Stearns-Reider, Kristen M.;Hicks, Michael R.;Hammond, Katherine G.;Reynolds, Joseph C.;Maity, Alok;Kurmangaliyev, Yerbol Z.;Chin, Jesse;Stieg, Adam Z.;Geisse, Nicholas A.;Hohlbauch, Sophia;Kaemmer, Stefan;Schmitt, Lauren R.;Pham, Thanh T.;Yamauchi, Ken;Novitch, Bennett G.;Wollman, Roy;Hansen, Kirk C.;Pyle, April D.;Crosbie, Rachelle H.
• 通讯作者: Crosbie, Rachelle H.

Single-cell RNA sequencing and binary hierarchical clustering define lung interstitial macrophage heterogeneity in response to hypoxia.

• DOI: 10.1152/ajplung.00104.2022
• 发表时间: 2022-07-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
• 影响因子: 4.9
• 作者: Campbell, Nzali, V;Mickael, Claudia;Kumar, Sushil;Zhang, Hui;Campbell, Ian L.;Gillen, Austin E.;Trentin, Caio O.;Diener, Katrina;Gao, Bifeng;Kheyfets, Vitaly O.;Gu, Sue;Kumar, Rahul;Phang, Tzu;Brown, R. Dale;Graham, Brian B.;Stenmark, Kurt R.
• 通讯作者: Stenmark, Kurt R.

Neonatal Selenoenzyme Expression Is Variably Susceptible to Duration of Maternal Selenium Deficiency.

• DOI: 10.3390/antiox10020288
• 发表时间: 2021-02-14
• 期刊: Antioxidants (Basel, Switzerland)
• 作者: Sherlock LG;Balasubramaniyan D;Zheng L;Zarate M;Sizemore T;Delaney C;Tipple TE;Wright CJ;Nozik-Grayck E
• 通讯作者: Nozik-Grayck E