Document text
Principal Investigator: Jinjiang Pang
Organization: UNIVERSITY OF ROCHESTER
Fiscal Year: 2022
Award: $466,903
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <(TNF)-α><21+ years old><Adult><Adult Human><Animal Model><Animal Models and Related Studies><Apoptosis><Apoptosis Pathway><Assay><Attenuated><Binding><Bioassay><Biologic Assays><Biological Assay><Biological Function><Biological Process><Blood Plasma><Blood Vessels><Blood monocyte><Cachectin><Cell Body><Cell Communication and Signaling><Cell Function><Cell Growth in Number><Cell Multiplication><Cell Process><Cell Proliferation><Cell Signaling><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cessation of life><Chronic><Common Rat Strains><Communication><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Death><Disease><Disorder><Dysfunction><Ectopic Expression><Endothelial Cells><External Domain><Extracellular Domain><Fibrosis><Functional disorder><Genetic mutation><Grant><Human><Human Genetics><Hypoxia><Hypoxic><IL-1><IL1><Immune><Immunes><Impairment><In Vitro><Inflammation><Interleukin I><Interleukin-1><Interleukins><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Ligands><Link><Lung><Lung Respiratory System><Lymphocyte-Stimulating Hormone><Macrophage Cell Factor><Macrophage-Derived TNF><Marrow monocyte><Mediating><Membrane><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Monocrotaline><Monocyte-Derived TNF><Murine><Mus><Null Mouse><Oxygen Deficiency><Pathogenesis><Pathologic Angiogenesis><Pathologic Neovascularization><Pathological Angiogenesis><Pathological Neovascularization><Patients><Physiopathology><Plasma><Plasma Serum><Programmed Cell Death><Progressive Disease><Rat><Rats Mammals><Rattus><Receptor Protein><Recombinants><Regulation><Reticuloendothelial System, Serum, Plasma><Role><Sequence Alteration><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Subcellular Process><T Helper Factor><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Therapeutic Effect><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vascular Endothelial Cell><Vascular remodeling><adulthood><base><biological signal transduction><cytokine><experience><genomic alteration><hemodynamics><improved><in vivo><inhibitor><lipid based nanoparticle><lipid nanoparticle><lung artery blood pressure><lung microvascular endothelial cells><lymphocyte activating factor><mRNA Expression><membrane structure><model of animal><model organism><monocyte><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><notch><notch protein><notch receptors><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><pressure in pulmonary arteries><prevent><preventing><protein expression><pulmonary><pulmonary arterial blood pressure><pulmonary arterial hypertension><pulmonary arterial pressure><pulmonary artery hypertension><pulmonary artery pressure><pulmonary artery systolic pressure><pulmonary microvascular endothelial cells><receptor><right heart failure><right sided heart failure><right ventricle failure><right ventricular failure><right ventricular heart failure><siRNA><social role><systemic inflammation><systemic inflammatory response><vascular><vascular constriction><vasoconstriction>