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Principal Investigator: Camilla Ferreira Wenceslau
Organization: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
Fiscal Year: 2024
Award: $372,500
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY WENCESLAU, CAMILLA F.
One of the major pathophysiological characteristics of hypertension is the presence of vascular
remodeling. Accordingly, it has been shown that 100% hypertensive subjects present small artery remodeling.
However, there is a gap in the literature in understanding the exact trigger that leads to vascular remodeling, and
this may limit our ability to adequately treat and prevent hypertension.
Recent evidence implicates immune mechanisms in the pathophysiology of hypertension. Formyl peptide
receptor (FPR)-1 is a pattern recognition receptor which plays a crucial role in the function of the innate immune
system. In fact, one of the most powerful signaling pathways that induces actin polymerization and neutrophil
movement is mediated by FPR-1. Recently, we observed that this receptor is expressed in arteries. Therefore,
we questioned why a receptor that is crucial for immune defense and cell motility in leukocytes, would be
expressed and functional in arteries? We observed that activation of FPR-1 in arteries is important for the
temporal reorganization of actin, which rapidly induces actin polymerization.
FPR-1 is a G-protein-coupled receptor that can bind N-formyl peptides produced by bacterial
degradation. Interestingly, mitochondria carry hallmarks of their bacterial ancestry. Consequently, both
mitochondrial and bacterial-derived peptides have a formyl group at their N-terminus. Therefore, N-formyl
peptides (NFPs), regardless of origin, are recognized by FPR-1 as pathogens and thus play a role in the initiation
of inflammation. Here, we observed for the first time that NFPs are present in the circulation of hypertensive
animals and humans. Therefore, it is plausible to suggest that synergistic action of leaky gut-derived bacteria
NFPs and cell damage-derived mitochondria NFPs lead to FPR-1 activation. Consequently, FPR-1 activation
maybe the trigger to induce vascular remodeling, via actin polymerization, and subsequently, hypertension.
This planned research is uniquely suited to the NHLBI Early Stage Investigator (ESI)-Research Project
Grant (R01). It is innovative and has a strong, translational and multi-disciplinary research team of collaborators
that have the capabilities and expertise to make this project successful. As an independent ESI, my short-term
goal is to use state-of-art approaches, including culture-pressure myographs, genetic-engineering technologies,
and arteries from humans and animals to explore a major driving force behind vascular-immune network
dysfunction in hypertension.
Terms: <21+ years old><Actins><Adult><Adult Human><Advanced Development><Affect><Animal Model><Animal Models and Related Studies><Animals><Aorta><Arteries><Attention><BP reduction><Bacteria><Binding><Biological Markers><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Pressure><Blood Vessels><Blood leukocyte><Body Tissues><Cell Body><Cell Death><Cell Locomotion><Cell Migration><Cell Movement><Cells><Cellular Migration><Cellular Motility><Cellular injury><Characteristics><Chemoattractant Receptor><Chemotactic Peptide Receptor><Chronic><Circulation><Common Rat Strains><Data><Dependence><Dysfunction><F-Chemotactic Peptide Receptor><FMLP Receptor><FPR1><FPR1 gene><Female><Formyl Peptide Receptor 1><Formyl Peptide Receptors><Functional disorder><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Germ-Free><Goals><Human><Hypertension><Immune><Immune system><Immunes><Immunobiology><Immunophysiology><Inflammation><Infusion><Infusion procedures><Initiation Factors><Innate Immune System><Interdisciplinary Research><Interdisciplinary Study><Intestinal Leakage><Intrinsic factor><Investigators><KO mice><Knock-out Mice><Knockout Mice><Lead><Leaky Gut><Leukocytes><Leukocytes Reticuloendothelial System><Link><Lipopolysaccharides><Literature><Maintenance><Marrow Neutrophil><Marrow leukocyte><Mediating><Mesenteric><Mesentery><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular><Molecular Interaction><Motility><Movement><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><N-Formylmethionyl Peptide Receptor><N-Formylpeptide Receptor><N-formyl Hexapeptide Receptor><NHLBI><National Heart, Lung, and Blood Institute><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Null Mouse><Patients><Pattern recognition receptor><Pb element><Peptide Initiation Factors><Peptides><Physiopathology><Play><Polymers><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><R-Series Research Projects><R01 Mechanism><R01 Program><Rat><Rats Mammals><Rattus><Receptor Activation><Receptor Protein><Recombinant DNA Technology><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Resistance><Role><Sentinel><Signal Pathway><Source><Technology><Testing><Therapeutic><Time><Tissues><Translation Initiation Factor><Translational Initiation Factor><Vascular Diseases><Vascular Disorder><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular remodeling><White Blood Cells><White Cell><adult animal><adulthood><antagonism><antagonist><bio-markers><biologic marker><biomarker><blood pressure elevation><blood pressure reduction><blood vessel disorder><body movement><cell damage><cell injury><cell motility><cellular damage><cofilin><damage to cells><driving force><elevated blood pressure><fMet-Leu-Phe receptor><formyl peptide><genetically engineered><heavy metal Pb><heavy metal lead><high blood pressure><high salt diet><high sodium diet><hyperpiesia><hyperpiesis><hypertensive><hypertensive disease><hypertensive disorder><increase in blood pressure><increased blood pressure><infusions><injury to cells><injury to the vasculature><innate immune function><innovate><innovation><innovative><juvenile animal><lower BP><lower blood pressure><lowers blood pressure><male><mature animal><microbial consortia><microbial flora><microbiota><microflora><mitochondrial><model of animal><multispecies consortia><necrocytosis><network dysfunction><neutrophil><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><normotensive><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathogen><pathophysiology><polymer><polymeric><polymerization><pressure><prevent><preventing><receptor><reduce BP><reduce blood pressure><reduction in BP><reduction in blood pressure><resistant><sensor><sex><social role><vascular><vascular dysfunction><vascular injury><vasculopathy><white blood cell><white blood corpuscle><young animal><zonulin>