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Principal Investigator: Cenk Ayata
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $658,720
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY/ABSTRACT
Despite intense research, we lack even the most basic understanding of how structural and functional changes
in small vessel diseases of the brain (SVD) are linked to tissue oxygenation, whether this results in tissue
hypoxia (O2 supply-demand mismatch), and how different microvascular segments contribute to this mismatch
in different brain areas. Leveraging our cutting-edge optical imaging tools for absolute pO2, blood flow, Ca2+
signaling, and microvascular morphology, and a clinically relevant CADASIL mouse model, we propose to
examine for the first time a causal link between microvascular dysfunction and O2 supply-demand mismatch.
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is
the most common monogenic inherited form of SVD leading to dementia, caused by mutations in Notch3.
Transgenic models of CADASIL recapitulate many clinical and histopathological hallmarks of the disease,
including early signs of SVD such as impaired CBF and functional hyperemic responses, and functional and
structural abnormalities in both arterioles and capillaries.
We will quantify absolute intravascular and tissue pO2, metabolic rate of O2 (CMRO2), CBF and capillary red
blood cell flux, and microvascular morphology, at rest and during functional brain activation, in both gray and
white matter, longitudinally over months, in unanesthetized CADASIL transgenic mice. Aim 1 will test whether
CADASIL causes age-dependent O2 supply-demand mismatch, manifested in islets of tissue hypoxia at rest or
during functional activation. Combining two-photon microscopy and optical coherence tomography (OCT), we
will test whether CADASIL leads to abnormal capillary red blood cell flux and increased capillary transit time
heterogeneity causing O2 supply-demand mismatch even before a reduction in absolute CBF becomes
manifest. Finally, we will examine whether O2 supply-demand mismatch can be corrected by genetic,
pharmacological, and immunological manipulations. Aim 2 will test whether CADASIL causes Ca2+
dysregulation in vascular smooth muscle and pericytes and whether it can be corrected by genetic,
pharmacological and immunological manipulations. Aim 3 will integrate the measurements from Aims 1 and 2
and construct a numerical model of oxygen advection and diffusion based on measured microvascular
morphology, reactivity, perfusion, and oxygenation. The model will relate structural and functional
microvascular changes to tissue O2 supply-demand mismatch, quantify the contribution and predict the limits of
the arteriolar and capillary compartments to support tissue oxygenation below which O2 supply-demand
mismatch develops. The model will thus shed light on all other SVDs (e.g. hypertension, amyloid). Altogether,
this proposal aims to fill significant gaps in our understanding of the mechanisms of microvascular dysfunction
in CADASIL, and will inform the vascular mechanisms of progressive neurodegeneration and cognitive
impairment in more common forms of SVD as well as in Alzheimer’s disease and related dementias.
Terms: <2-photon microscopy><AD related dementia><ADRD><Adventitial Cell><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Amentia><Amyloid><Amyloid Substance><Animal Genetics><Animal Model><Animal Models and Related Studies><Antibodies><Apoplexy><Area><Arterial Disorder><Arteriopathy><Binswanger Disease><Binswanger Encephalopathy><Blood Vessels><Blood capillaries><Blood erythrocyte><Blood flow><Body Tissues><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><Brain Vascular Accident><Brain region><Cell Communication and Signaling><Cell Signaling><Cerebral Stroke><Cerebral small vessel disease><Cerebrovascular Apoplexy><Cerebrovascular Circulation><Cerebrovascular Stroke><Cerebrum><Chronic Progressive Subcortical Encephalopathy><Clinical><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Cortical vasculature><DT-R><DTR gene><Data><Dementia><Diffusion><Diphtheria Toxin Receptor (Heparin-Binding EGF-Like Growth Factor) Gene><Diphtheria Toxin Receptor Gene><Diphtheria Toxin Sensitivity Gene><Disease><Disorder><Disturbance in cognition><Doppler OCT><Drosophila Homolog of NOTCH 3><Dysfunction><EGF><EGF Receptor><EGF gene><EGFR><ERBB Protein><Encephalon><Encephalon Diseases><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Equilibrium><Erythrocytes><Erythrocytic><Exhibits><Functional disorder><Genetic><Genetic Alteration><Genetic Change><Genetic defect><HB-EGF><HBEGF><HEGFL><HER1><Heparin-Binding EGF-Like Growth Factor Gene><Hereditary><Heterogeneity><Hyperemia><Hypertension><Hypoxia><Hypoxic><Imaging Device><Imaging Instrument><Imaging Tool><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Impaired cognition><Impairment><Inherited><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Knowledge><Leiomyocyte><Link><Maps><Marrow erythrocyte><Measurement><Measures><Mice><Mice Mammals><Microscopy><Microvascular Dysfunction><Modeling><Molecular><Morphology><Murine><Mus><Mutation><NOTCH3><NOTCH3 gene><O element><O2 element><OCT Tomography><Optical Coherence Tomography><Optics><Oxygen><Oxygen Deficiency><Passive Immunization><Pathway interactions><Perfusion><Pericapillary Cell><Pericytes><Perivascular Cell><Physiopathology><Publishing><Red Blood Cells><Red Cell><Research><Resolution><Rest><Rouget Cells><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Stroke><Structural defect><Structural malformation><Subcortical Arteriosclerotic Encephalopathy><Subcortical Infarctions><Subcortical Infarcts><Subcortical Leukoencephalopathy><TGF-alpha Receptor><TIMP-3><TIMP3><TIMP3 gene><Testing><Time><Tissue Inhibitor of Metalloproteinase-3><Tissues><Transforming Growth Factor alpha Receptor><Transgenic Mice><Transgenic Model><Trees><Urogastrone Receptor><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular Smooth Muscle><Visualization><Work><age associated><age correlated><age dependent><age linked><age related><age specific><arteriole><autosome><awake><balance><balance function><biological signal transduction><blood corpuscles><blood flow in brain><brain attack><brain blood circulation><brain blood flow><brain tissue><c-erbB-1><c-erbB-1 Protein><capillary><cardiac disease induced cognitive impairment><cerebral><cerebral blood flow><cerebral circulation><cerebral small vessel disorder><cerebral vascular accident><cerebrocirculation><cerebrovascular accident><cerebrovascular blood flow><clinical relevance><clinically relevant><cognitive dysfunction><cognitive loss><cortical blood vessels><cortical microvascular><cortical microvessels><cortical vascular><cortical vessels><develop therapy><diffused><diffuses><diffusing><diffusions><disability><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><genome mutation><gray matter><hemodynamics><high blood pressure><human disease><human model><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><innovative technologies><insight><intervention development><islet><metabolic rate><microvascular complications><microvascular disease><model of animal><model of human><mouse model><multi-modality><multimodality><murine model><mutant><novel><novel imaging technology><optic imaging><optical><optical Doppler tomography><optical coherence Doppler tomography><optical imaging><passive vaccination><pathophysiology><pathway><pharmacologic><progressive neurodegeneration><proto-oncogene protein c-erbB-1><resolutions><response><small vessel disease><stroked><strokes><structural abnormalities><structural anomalies><substantia alba><substantia grisea><therapy development><tissue degeneration><tissue oxygen saturation><tissue oxygenation><tool><transgenic trait><treatment development><two photon excitation microscopy><two photon microscopy><vascular><vascular cognitive impairment and dementia><vascular contributions to cognition/dementia><vascular contributions to cognitive impairment and dementia><white matter>