Document text
Principal Investigator: Ethan Lippmann
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2024
Award: $443,089
Funding agency: National Institute of Neurological Disorders and Stroke
Summary statement
Robust model systems are essential for understanding human disease. While Alzheimer’s disease can be studied using in vivo models that have become more representative in recent years (e.g. by introducing natural genetic diversity and humanized APOE variants into existing Alzheimer’s mouse models), the ability to study vascular contributions to cognitive impairment and dementia (VCID) and cerebral small vessel disease (SVD) remains difficult. Indeed, the molecular mechanisms underlying VCID and SVD remain mostly unknown, and in vivo models for these diseases are lacking. A representative human in vitro model would therefore be beneficial to complement in vivo systems and improve understanding of vascular contributions to neurodegeneration. The development of human induced pluripotent stem cell (iPSC) technology has increased the utility of in vitro central nervous system (CNS) models, which have gradually progressed from isolated two-dimensional cell cultures to multi-cellular three-dimensional assemblies that better recapitulate the organization and architecture of specific brain regions. However, these human ‘brain organoids’ still have significant deficits. Notably, cortical organoids exhibit improperly organized laminar architectures and lack perfusable microvasculature with blood-brain barrier (BBB) function. These deficits limit the representativeness of using brain organoids to understand the mechanisms of VCID and SVD. In this proposed project, we will develop a biomimetic brain organoid platform with robust neurovascular function. Aim 1 of this proposal will characterize the organization and maturation of cortica. organoids grown in a novel biomaterial that mimics cues provided by radial glia to help guide laminar patterning. Aim 2 will focus on integrating brain endothelial cells and pericytes with the cortical organoids to develop perfusable microvasculature throughout the tissue construct, thereby generating the ‘neurovascular organoid’ platform. Aim 3 will then validate the representativeness of the neurovascular organoids by subjecting them to acute and chronic injuries known to damage the BBB; in particular, iPSCs with defined APOE genotype will be used to assess onset and progression of neurovascular dysfunction in response to this well-established genetic risk factor. Overall, this project will establish a human in vitro model of the vascularized cortex that is expected to have utility for unraveling the mechanisms of VCID and SVD.
Terms: <2-dimensional><3-D><3-Dimensional><3D><AD dementia><Academic Medical Centers><Acute><Adventitial Cell><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease risk><Alzheimers Dementia><Animal Model><Animal Models and Related Studies><Animals><Antigenic Determinants><Architecture><Assay><BBB disruption><BBB function><Binding Determinants><Bioassay><Biocompatible Materials><Biologic Models><Biological Assay><Biological Mimetics><Biological Models><Biomaterials><Biomimetics><Blood - brain barrier anatomy><Blood Vessels><Blood capillaries><Blood-Brain Barrier><Body Tissues><Brain><Brain Nervous System><Brain region><CNS Diseases><CNS Nervous System><CNS disorder><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Line><Cell Signaling><CellLine><Cells><Central Nervous System><Central Nervous System Diseases><Central Nervous System Disorders><Cerebral small vessel disease><Chronic><Complement><Complement Proteins><Coupled><Cues><Data><Degenerative Neurologic Disorders><Development><Disease><Disorder><Drug Evaluation><Drug Evaluation Studies><Drug toxicity><Drug usage><Dysfunction><Electrophysiology><Electrophysiology (science)><Encephalon><Endothelial Cells><Engineering><Engineering / Architecture><Epitopes><Exhibits><Fore-Brain><Forebrain><Functional disorder><Gelatin><Generalized Growth><Genetic Diversity><Genetic Variation><Genetic predisposing factor><Genotype><Glia><Glial Cells><Growth><Health><Hemato-Encephalic Barrier><Human><Human Biology><Hydrogels><Image><In Vitro><Induced pluripotent stem cell derived neurons><Injury><Intracellular Communication and Signaling><Investigation><Ischemia-Reperfusion Injury><Kolliker's reticulum><Methacrylates><Microfabrication><Microvascular Dysfunction><Model System><Modeling><Modern Man><Molecular><N-Cadherin><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroglia><Neuroglial Cells><Neurologic><Neurologic Degenerative Conditions><Neurological><Neuron Degeneration><Neuron from iPSC><Neuron from induced pluripotent stem cells><Neurons><Neurophysiology / Electrophysiology><Non-neuronal cell><Nonneuronal cell><Organoids><Outcome Measure><Pattern><Peptides><Pericapillary Cell><Pericytes><Perivascular Cell><Physiologic><Physiological><Physiopathology><Polymers><Primary Senile Degenerative Dementia><Prosencephalon><Radial><Radius><Reperfusion Damage><Reperfusion Injury><Research Resources><Resources><Rouget Cells><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Strains Cell Lines><Structure><Synapses><Synaptic><System><Techniques><Technology><Therapeutic><Time><Tissue Growth><Tissue constructs><Tissues><Toxicology><Universities><University Medical Centers><Variant><Variation><Vascularization><Work><alzheimer risk><angiogenesis><biological material><biological signal transduction><blood damage><blood-brain barrier disruption><blood-brain barrier function><bloodbrain barrier><bloodbrain barrier disruption><bloodbrain barrier function><brain endothelial cell><brain microvascular endothelial cell><brain vascular endothelial cell><brain vascularization><capillary><cardiac disease induced cognitive impairment><cell culture><cell cultures><cerebral endothelial cell><cerebral microvascular endothelial cell><cerebral small vessel disorder><cerebral vascular endothelial cell><cerebral vascularization><complementation><cultured cell line><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><density><developmental><differentiation of pluripotent stem cells><disease mechanisms study><disease model><disease phenotype><disorder model><drug discovery><drug efficacy><drug use><electrophysiological><functional outcomes><genetic risk factor><hiPSC><human disease><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><hydrogel scaffold><iPS><iPS neurons><iPSC><iPSC derived-neurons><iPSC technology><iPSCs><imaging><improved><in vitro Model><in vivo><in vivo Model><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cell neurons><induced pluripotent stem cell technology><inducible pluripotent stem cell><inherited factor><injuries><measurable outcome><microvascular complications><microvascular disease><mimetics><model of animal><mouse model><murine model><nerve cement><neural><neural circuit><neural circuitry><neural degeneration><neural patterning><neuro-vascular><neuro-vascular damage><neuro-vascular injury><neurocircuitry><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal><neuronal degeneration><neurons derived from induced pluripotent stem cells><neurovascular><neurovascular damage><neurovascular injury><novel><ontogeny><outcome measurement><pathophysiology><pluripotent stem cell differentiation><polymer><polymeric><prevent><preventing><primary degenerative dementia><prospective><response><senile dementia of the Alzheimer type><small vessel disease><synapse><synaptic circuit><synaptic circuitry><three dimensional><two-dimensional><vascular><vascular cognitive impairment and dementia><vascular contributions><vascular contributions to cognition/dementia><vascular contributions to cognitive impairment and dementia>