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Signal transduction mechanisms that mediate normal and pathologic angiogenesis

介导正常和病理性血管生成的信号转导机制

基本信息

批准号：
9886420
负责人：
Jinjiang Pang
金额：
$ 43.83万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-04 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886420
关键词：
Adult Animal Model Apoptosis Attenuated Binding Biological Assay Biological Process Blood Vessels Cell Proliferation Cell physiology Cells Cessation of life Chronic Cleaved cell Communication DNA Sequence Alteration Data Disease Ectopic Expression Endothelial Cells Extracellular Domain Fibrosis Functional disorder Grant Heart failure Human Human Genetics Hypoxia Immune Impairment In Vitro Inflammation Interleukin-1 Interleukins Knockout Mice Knowledge Ligands Link Lipids Lung Mediating Membrane Modeling Molecular Monocrotaline Mus Pathogenesis Pathologic Neovascularization Patients Plasma Progressive Disease Rattus Recombinants Regulation Role Signal Transduction Small Interfering RNA TNF gene Testing Therapeutic Therapeutic Effect Vascular Endothelial Cell Vascular remodeling base cytokine experience hemodynamics improved in vivo inhibitor/antagonist mRNA Expression monocyte nanoparticle notch protein novel novel therapeutic intervention novel therapeutics pressure prevent protein expression pulmonary arterial hypertension receptor vasoconstriction

项目摘要

Title of the grant Signal transduction mechanisms that mediate normal and pathologic angiogenesis Abstract Pulmonary arterial hypertension (PAH) is a progressive disease, characterized by vasoconstriction, cell proliferation, and fibrosis, leading to elevated pulmonary arterial pressure and often causing right heart failure and death. There is no cure for this disease. Therefore, novel mechanistic studies and new therapeutic strategies are urgently needed. Elevation of plasma cytokines in PAH patients is a hallmark of inflammation. As the major effector, monocytes release cytokines and infiltrate in perivascular regions of the lung. Depletion of monocytes attenuates vascular remodeling and hemodynamic changes in PAH animal models. This evidence implies a communication between monocytes and endothelial cells (ECs). However, the underlying mechanisms are not well understood. The objective of the current proposal is to define the role of extracellular domain of cleaved delta like 4 (exDll4) in the pathogenesis of PAH and its mechanisms. In vitro, we discovered that calpain1 can cleave Dll4. We also found that TNF and IL-1 increases Dll4 expression, Dll4 cleavage in human monocyte, and exDll4 release from monocytes. Furthermore, we found that recombinant exDll4 significantly increased apoptosis and decreased barrier function in ECs. Seeking the mechanism of action, we found exDll4 associated with intact Dll4, and this interaction prevents Dll4 binding to Notch1 and thus inhibits Notch1 activation. In vivo, we found that Dll4 expression and exDll4 release in monocyte are significantly elevated in PAH mice as well as in PAH patients. However, Notch1 signaling is decreased in lungs during PAH progression in mice and rats. Based on these findings, we hypothesize that exDll4 derived from monocytes is crucial for PAH progression by inducing apoptosis and impairing barrier function in lung EC. Mechanistically, exDll4 forms a heterodimer with Dll4 to prevent the association of Dll4 and Notch1, blocking Notch1 signaling. To test our hypothesis, we propose three aims. Aim 1. Define the regulatory mechanisms of Dll4 expression and exDll4 release from monocyte in PAH. Aim 2. Determine the biological function of exDll4-Notch1 in lung EC and its molecular mechanisms. Aim 3. Characterize the therapeutic effects of inhibiting monocyte Dll4 on PAH progression. Accomplishing these aims will 1) fill the knowledge gap regarding the mechanisms of vascular remodeling and EC dysfunction in the pathogenesis of PAH mediated by monocyte derived exDll4; 2) reveal the regulation of Dll4 cleavage; and 3) invent a novel therapeutic strategy for PAH by targeting monocyte Dll4.

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