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Principal Investigator: KRZYSZTOF KUCZERA
Organization: UNIVERSITY OF KANSAS LAWRENCE
Fiscal Year: 2024
Award: $487,741
Funding agency: National Institute on Aging
PROJECT SUMMARY
Delivering molecules across the blood-brain barrier (BBB) represents a major challenge in treating mental
disorders and central nervous system (CNS) disorders. Many therapeutic agents that have the potential to treat
these disorders have difficulty entering the brain due to the presence of the BBB. In this project, we are
responding to the NIH PAR-22-031 that calls for development of delivery systems that can target drugs to the
brain. We have recently developed BBB modulators (BBBMs) that significantly increase in vivo brain delivery of
small-to-large drug molecules including therapeutic peptides and proteins. Recently, BBBMs (i.e., HAVN1 and
DWI peptides) have been shown to selectively modulate the BBB over the peripheral vasculatures in the in vitro
and in vivo systems. Our hypothesis is that these BBBMs enhance brain delivery of therapeutic proteins by
modulating cadherin-mediated cell-cell adhesion in the paracellular pathway of the BBB. The overall goal of this
project is aimed at developing and optimizing the next generation of BBBMs as a novel and non-invasive delivery
system to target drugs to the brain. BBBMs transiently increase the porosity of the BBB paracellular pathways
to allow drugs to enter the brain from the bloodstream. To accomplish the overall goal, we will pursue the
following Specific Aims. First, a combination of virtual screening and 3D in vitro models of the BBB vs. peripheral
vasculatures will be used to optimize modulatory activity and selectivity of the next generation of BBBMs from
VE-cadherin. Second, DMPK profiles, toxicity, and selectivity of BBBMs will be evaluated using animal models.
Toxicity of BBBMs in various organs will be determined. Third, the biological effects of BBBMs-facilitated brain
delivery of FL-BDNF and BDNF peptides will be evaluated in mouse models of both sporadic and familial
Alzheimer's disease (AD). The biological effects of FL-BDNF and BDNF peptides in the brain will be assessed
by determining TrkB signaling, synaptic activity, AD neuropathology, and learning and memory. If successful,
this project will have impacts on (a) reversing neurodegeneration, (b) improving diagnosis and treatment of brain
diseases and injuries, (c) expanding our understanding of how the brain works at both the cellular and molecular
levels, and (d) designing new tools for monitoring brain function in vivo.
Terms: <3-D><3-Dimensional><3D><7B4 Antigen><7B4 protein><AD dementia><APOE e4><APOE-ε4><APOEε4><APP-PS1><APP/PS1><Acquired brain injury><Affect><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Animal Disease Models><Animal Model><Animal Models and Related Studies><Animals><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><BBB crossing><BDNF><Binding><Biological><Blood><Blood - brain barrier anatomy><Blood Circulation><Blood Reticuloendothelial System><Blood-Brain Barrier><Bloodstream><Brain><Brain Diseases><Brain Disorders><Brain Injuries><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><Brain-Derived Neurotrophic Factor><CD144 Antigen><CNS Diseases><CNS Nervous System><CNS disorder><Cadherins><Cancer Drug><Cell Body><Cell Communication and Signaling><Cell Junctions><Cell Signaling><Cell-Cell Adhesion><Cells><Central Nervous System><Central Nervous System Diseases><Central Nervous System Disorders><Chemical Structure><Clinical Research><Clinical Study><Clinical Treatment Moab><Complex><Computer Models><Computerized Models><Cytoplasm><Development><Diagnosis><Diagnostic><Diffusion><Disease><Disorder><Disseminated Sclerosis><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Targeting><Drug Transport><Drugs><Effectiveness><Encephalon><Encephalon Diseases><Endothelial Cells><Enzyme Gene><Enzymes><Goals><Hemato-Encephalic Barrier><Human><In Vitro><Intercellular Junctions><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><KI mice><Knock-in Mouse><Lead><Learning><Left><Length><Mediating><Medication><Medulloblastoma><Memory><Mental disorders><Mental health disorders><Methods><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Molecular Probes><Monitor><Monoclonal Antibodies><Multiple Sclerosis><Murine><Mus><NIH><National Institutes of Health><Neoplastic Disease Chemotherapeutic Agents><Nerve Degeneration><Nervous System Diseases><Nervous System Disorder><Neuraxis><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Occluding Junctions><Organ><Pathway interactions><Patients><Pb element><Peptide-based drug><Peptides><Peripheral><Pharmaceutical Preparations><Pharmacokinetics><Porosity><Primary Senile Degenerative Dementia><Property><Proteins><Psychiatric Disease><Psychiatric Disorder><Recurrent disease><Relapsed Disease><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Synapses><Synaptic><System><Therapeutic><Therapeutic Agents><Tight Junctions><Toxic effect><Toxicities><Tumor-Specific Treatment Agents><United States National Institutes of Health><VE-Cadherin><Vascular Endothelial Cadherin><Vascular Endothelial Cadherin 1><Work><Zonula Occludens><age associated neurodegeneration><age associated neurodegenerative disease><age associated neurodegenerative disorder><age dependent neurodegeneration><age dependent neurodegenerative condition><age dependent neurodegenerative disease><age dependent neurodegenerative disorder><age related neurodegeneration><age-driven neurodegenerative disorders><age-related neurodegenerative disease><age-related neurodegenerative disorder><aging associated neurodegeneration><aging associated neurodegenerative disease><aging related neurodegeneration><aging related neurodegenerative disease><aging related neurodegenerative disorder><anti-cancer drug><apo E-4><apo E4><apo epsilon4><apoE epsilon 4><apoE-4><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-4><apolipoprotein E4><biologic><biological signal transduction><blood-brain barrier crossing><bloodbrain barrier><bloodbrain barrier crossing><brain damage><brain microvasculature><brain microvessels><brain pathway><brain-injured><cadherin 5><cerebral microvasculature><cerebral microvessels><cognitive function><computational modeling><computational models><computer based models><computerized modeling><design><designing><developmental><diffused><diffuses><diffusing><diffusions><drug metabolism><drug/agent><familial AD><familial Alzheimer><familial Alzheimer disease><heavy metal Pb><heavy metal lead><improved><in vitro Model><in vivo><insular sclerosis><knockin mice><lab simulation><laboratory simulation><mAbs><mental illness><model of animal><monoclonal Abs><mouse model><murine model><mutant><nano particle><nano-sized particle><nanoparticle><nanosized particle><native protein drug><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neurological disease><neuronal degeneration><neuropathologic><neuropathological><neuropathology><neurotrophic factor><neurotrophin><neutrophin><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><occludin><pathway><peptide drug><pharmaceutical protein><pre-clinical><preclinical><prevent><preventing><primary degenerative dementia><programs><protein drug agent><protein-based drug><psychiatric illness><psychological disorder><senile dementia of the Alzheimer type><siRNA><synapse><therapeutic peptide><therapeutic protein><three dimensional><tool><tumors in the brain><virtual experiments><virtual screening><virtual screenings>