Complement Mediated Remodeling in Pulmonary Vascular Disease
肺血管疾病中补体介导的重塑
基本信息
- 批准号:10470731
- 负责人:
- 金额:$ 275.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAgeAnimal ModelAnimalsAutomobile DrivingBiological MarkersBiological ModelsBlood PlateletsBlood VesselsCattleCellsCessation of lifeChimeric ProteinsChronicClinicalComplementComplement ActivationDevelopmentDiagnosisDiseaseDisease ProgressionEndotheliumEnvironmentExperimental Animal ModelExtracellular MatrixGenetic TranscriptionGoalsHeterogeneityHumanHypoxiaImageImmunityImmunoglobulinsIndividualInflammationInflammatoryInterventionInvestigationLeadLesionLinkLungMass Spectrum AnalysisMediatingMethodologyModelingMolecularMolecular ProfilingMonoclonal AntibodiesMorbidity - disease rateMouse ProteinMusNatural ImmunityPathogenesisPathogenicityPathologicPatientsPhenotypePlatelet ActivationPlayPositioning AttributeProcessProteomeProteomicsPulmonary HypertensionPulmonary arterial remodelingRattusResearch PersonnelResolutionRoleSU 5416SchistosomaSchistosomiasisShapesSignal TransductionSiteT-LymphocyteTechniquesTestingThrombospondin 1TissuesTransplantationUnited States Food and Drug AdministrationVascular remodelingadaptive immunityantibody detectioncirculating biomarkerscomplement pathwaydisease heterogeneityextracellularhypoxia-induced pulmonary hypertensionin vivoindividualized medicineinhibitorlung vascular inflammationmacrophagemonocytemortalityneoantigensnovelnovel therapeuticspulmonary arterial hypertensionpulmonary vascular disorderrecruitsextranslational goaltreatment response
项目摘要
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)困扰着两种性别和广泛年龄范围的患者,并且高度相关。
致命的,如果不及时诊断和适当治疗。尽管在理解其
发病机制和美国食品和药物管理局批准的14种治疗方法的发展
(FDA)在过去的二、三十年里,它仍然与高发病率和死亡率有关。的
本PPG的基本前提是PAH在临床参数方面具有高度异质性,包括
启动因素、临床表现、进展速度和对治疗的反应。重要的是,患者对
患者异质性,包括肺血管病变的类型和相应的内型(即,
驱动特定疾病表现的潜在分子过程),已经被我们的小组发现
并揭示了疾病发病机制的高度复杂性。对这些更广泛的问题缺乏调查,
异质性方面导致缺乏对特定子系统的具体因素的理解,
PAH的表型-对更有针对性(和个性化)治疗的开发产生负面影响。
这些局限性表现在这样一个事实上,即一些患者在目前可用的治疗中存活多年-
而另一些人则从发病到移植迅速而无情地进展
或者死亡该提案旨在揭示与肺血管炎症相关的新的发病过程,
重塑,以及PH中肺血管病变的分子基础,同时认识到
疾病的病理学和病理生物学异质性。在这方面要检验的中心前提是,
建议是早期和持续的局部、肺血管特异性补体激活导致
持续的血管周围炎症和细胞外基质变化,从而形成前馈
促炎症/促重塑血管周围微环境的环,导致
博士这一应用代表了朝着确定新的生物标志物和更有效的方法迈出的重要一步。
个性化治疗,这是非常必要的。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kurt R. Stenmark其他文献
Glycolytic Metabolism of Fibrocytes Derived from Distal Pulmonary Artery Wall of Chronic Hypoxia-Induced Pulmonary Hypertensive Neonatal Calves Exhibit Increased Oxidative Stress
- DOI:
10.1016/j.freeradbiomed.2012.10.157 - 发表时间:
2012-11-01 - 期刊:
- 影响因子:
- 作者:
Lydie Plecita;Petr Jezek;Min Li;Amanda R. Flockton;Michael E. Yeager;Kurt R. Stenmark - 通讯作者:
Kurt R. Stenmark
Kolorado Üniversitesi Tip Fakültesi, Tip Bölümü, Translasyonel Akciğer Araştirma Programi, Aurora, Kolorado, ABD;
Kolorado Üniversitesi Tip Fakültesi、Tip Bölümü、Translasyonel Akciğer Araştirma Programi、Aurora、Kolorado、ABD;
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
Rubin M. Tuder;Stephen L. Archer;Peter Dorfmüller;Serpil C. Erzurum;Christophe Guignabert;Evangelos D. Michelakis;Marlene Rabinovitch;Ralph T. Schermuly;Kurt R. Stenmark;NW Morrell - 通讯作者:
NW Morrell
Characterization of pulmonary arterial stiffness using cardiac MRI
- DOI:
10.1007/s10554-023-02989-6 - 发表时间:
2023-10-30 - 期刊:
- 影响因子:1.500
- 作者:
Michael T. Cain;Michal Schäfer;Sarah Park;Alex J. Barker;Daniel Vargas;Kurt R. Stenmark;Yen-Rei A. Yu;Todd M. Bull;D. Dunbar Ivy;Jordan R.H. Hoffman - 通讯作者:
Jordan R.H. Hoffman
Clasificación funcional de la hipertensión pulmonar en niños: informe del task force pediátrico del Pulmonary Vascular Research Institute (PVRI), Panamá 2011
血管研究所 (PVRI),巴拿马 2011 年
- DOI:
10.1016/s0120-5633(12)70156-0 - 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
Astrid E. Lammers;Ian Adatia;M. D. Cerro;G. Diaz;Alexandra Heath Freudenthal;F. Freudenthal;S. Harikrishnan;Dunbar Ivy;Antonio Augusto Lopes;J. U. Raj;Julio Sandoval;Kurt R. Stenmark;Sheila G. Haworth - 通讯作者:
Sheila G. Haworth
Consenso sobre la clasificación de la enfermedad vascular pulmonar hipertensiva en niños: Reporte del task force pediátrico del Pulmonary Vascular Research Institute (PVRI) Panamá 2011
Consenso sobre la clasificación de la enfermedad vasural pulmonar hipertensiva en niños: Reporte del 工作组儿科肺血管研究所 (PVRI) 巴拿马 2011
- DOI:
10.1016/s0120-5633(12)70157-2 - 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
M. D. Cerro;Steven H. Abman;G. Diaz;Alexandra Heath Freudenthal;F. Freudenthal;S. Harikrishnan;Sheila G. Haworth;D. Ivy;Antonio Augusto Lopes;J. U. Raj;Julio Sandoval;Kurt R. Stenmark;Ian Adatia;Astrid E. Lammers - 通讯作者:
Astrid E. Lammers
Kurt R. Stenmark的其他文献
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{{ truncateString('Kurt R. Stenmark', 18)}}的其他基金
Complement Mediated Remodeling in Pulmonary Vascular Disease
肺血管疾病中补体介导的重塑
- 批准号:
10686922 - 财政年份:2020
- 资助金额:
$ 275.42万 - 项目类别:
Immunoglobulin-Driven Activation of the Complement Cascade is a Critical Determinant of PAH Initiation and Progression
免疫球蛋白驱动的补体级联激活是 PAH 发生和进展的关键决定因素
- 批准号:
10470735 - 财政年份:2020
- 资助金额:
$ 275.42万 - 项目类别:
Complement Mediated Remodeling in Pulmonary Vascular Disease
肺血管疾病中补体介导的重塑
- 批准号:
10224327 - 财政年份:2020
- 资助金额:
$ 275.42万 - 项目类别:
Immunoglobulin-Driven Activation of the Complement Cascade is a Critical Determinant of PAH Initiation and Progression
免疫球蛋白驱动的补体级联激活是 PAH 发生和进展的关键决定因素
- 批准号:
10686929 - 财政年份:2020
- 资助金额:
$ 275.42万 - 项目类别:
Immunoglobulin-Driven Activation of the Complement Cascade is a Critical Determinant of PAH Initiation and Progression
免疫球蛋白驱动的补体级联激活是 PAH 发生和进展的关键决定因素
- 批准号:
10224331 - 财政年份:2020
- 资助金额:
$ 275.42万 - 项目类别:
Complement Mediated Remodeling in Pulmonary Vascular Disease
肺血管疾病中补体介导的重塑
- 批准号:
10024460 - 财政年份:2020
- 资助金额:
$ 275.42万 - 项目类别:
Crosstalk Between Metabolism and Inflammation in Pulmonary Hypertension
肺动脉高压代谢与炎症之间的串扰
- 批准号:
8800338 - 财政年份:2014
- 资助金额:
$ 275.42万 - 项目类别:
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