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Principal Investigator: Kostandin Pajcini
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $405,490
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Cells employ nanoscale mechanisms to secrete extracellular vesicles (EVs) that contain a variety of functional
ligands on the lipid membrane. This mode of delivery offers an effective strategy to systemically activate
membrane receptors over distance without a need for cell migration and juxtacrine interactions. However, the
intrinsic properties of EVs that enable this function and their mechanisms of action remain generally unclear.
To address these questions, we developed a facile strategy to functionalize EVs with defined multivalent
extracellular ligands that can activate specific cell membrane receptors to induce therapeutic effects. As a
proof-of-concept, we turned to the Notch pathway, since it employs a mechanistically direct, simple mechanism
of activation with direct transcriptional outcomes in the development and homeostasis of most vascularized
organs. Our preliminary data show that Notch ligand functionalized EVs but not synthetic liposomes with a
more rigid formulation reverse edema and vascular permeability after endotoxemia-induced injury in mice. We
also show that the ability of Notch ligand functionalized EVs to restore endothelial barrier function requires the
activation of the canonical Notch signaling pathway in endothelial cells. We will build on these results to test
the hypothesis that Notch ligand functionalized EVs therapeutically restore the endothelial barrier and tissue
function. In Aim 1, we will determine the ideal characteristics that enable Notch ligand functionalized EVs to
restore endothelial barrier integrity. We predict that EVs can sustain deformation during adhesion to cell
membrane receptors under mechanical force due to their unique lipid compositions and water flux capability,
thereby resulting in potent, yet specific activation of downstream pathways. In Aim 2, we will investigate how
Notch ligand loaded EVs restore the endothelial barrier after injury, which Notch receptor is activated, and what
gene targets are expressed. The project is highly multidisciplinary in that it will employ a combination of
expertise in nanotechnology, chemistry, membrane biophysics, cellular and molecular biology, and in vivo
approaches to address the specific aims. Success of the project will enable the generalization of EVs as
nanoscale therapeutic modalities to activate specific molecular pathways via multivalent ligand presentation
that lead to tissue repair and regeneration.
Terms: <Address><Adhesions><Aquaporins><Area><Atomic Force Microscopy><Autoregulation><Binding><Biocompatible Materials><Biological><Biology><Biomaterials><Biophysics><Blood Vessels><Body Tissues><Bone Marrow Ablation><Capsid Proteins><Cell Body><Cell Communication and Signaling><Cell Function><Cell Locomotion><Cell Membrane Lipids><Cell Migration><Cell Movement><Cell Physiology><Cell Process><Cell Signaling><Cell Surface Receptors><Cell membrane><Cell secretion><Cells><Cellular Function><Cellular Immune Function><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Cellular Secretion><Cellular biology><Characteristics><Chemistry><Chimera Protein><Chimeric Proteins><Coat Proteins><Cytoplasmic Membrane><DNA Molecular Biology><Data><Development><Dropsy><Edema><Endothelial Cells><Endothelium><Endotoxemia><Engineering><Evolution><Force Microscopy><Formulation><Fusion Protein><Gene Targeting><Gene Transcription><Genetic><Genetic Transcription><Goals><Hindlimb><Homeostasis><Hydrogen Oxide><Hydrops><Image><Inflammation><Injury><Intracellular Communication and Signaling><Investigators><Ischemia><Ligands><Lipids><Lipopolysaccharides><Liposomal><Liposomes><Lung><Lung Respiratory System><Mediating><Membrane><Membrane Lipids><Mice><Mice Mammals><Modality><Molecular><Molecular Biology><Molecular Interaction><Mouse Strains><Murine><Mus><Nanoplatform><Nanotechnological platform><Nanotechnology><Notch Signaling Pathway><Organ><Osmotic Pressure><Outcome><Pathway interactions><Physiological Homeostasis><Plasma Membrane><Property><Proteolysis and Signaling Pathway of Notch><RNA Expression><Receptor Activation><Receptor Protein><Reporter><Research Personnel><Researchers><Residual><Residual state><Scanning Force Microscopy><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Subcellular Process><Testing><Therapeutic><Therapeutic Effect><Tissues><Transcription><Vascular Permeabilities><Vascularization><Venus><Viral Coat Proteins><Viral Outer Coat Protein><Water><Water Channel Proteins><biologic><biological material><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><cell biology><cell motility><chemotherapy><design><designing><developmental><efficacy testing><experience><extracellular><extracellular vesicles><imaging><immune function><in vivo><inducible expression><inducible gene expression><inhibitor><injuries><injury to tissue><insight><interdisciplinary approach><mechanical force><member><membrane structure><mouse model><multidisciplinary><multidisciplinary approach><murine model><nano medicinal><nano medicine><nano meter scale><nano meter sized><nano tech><nano technology><nano vesicle><nano-technological><nanomedicinal><nanomedicine><nanometer scale><nanometer sized><nanoscale><nanotech><nanotechnological><nanotechnology platform><nanovesicle><notch><notch protein><notch receptors><pathway><plasmalemma><public health relevance><pulmonary><receptor><reconstitute><reconstitution><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><regenerative><response><restoration><success><surface coating><technology platform><technology system><tissue injury><tissue regeneration><tissue regrowth><tissue renewal><tissue repair><tissue specific regeneration><uptake><vascular><water channel><water transporter>