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Principal Investigator: Manfred Boehm
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $658,626
Funding agency: National Heart Lung and Blood Institute
Brain microvascular ischemic disease is a common cause of leukoencephalopathy, leading to cognitive
impairment, dementia, and stroke. CADASIL (cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy) is the most frequent mendelian cause of cerebral small vessel
disease. Over two decades ago, disease-causing CADASIL mutations were identified in the receptor
NOTCH3. These mutations result in progressive degeneration of vascular smooth muscle cells in
arterioles. While systemic in nature, the clinical deficits associated with CADASIL manifest primarily in
the brain as a vascular disease, leading to multifocal ischemia with progressive cognitive decline. Despite
its devastating impact on patients, our knowledge of the disease is limited, restricting targeted
therapeutic strategies. A major impediment to progress has been the wide variability in disease
manifestation and a lack of agreement as to whether CADASIL results from a gain or loss of function in
NOTCH3 signaling.
Through a collaborative effort with the NIH Clinical Center, we have made significant strides towards
defining a broader range of clinical read-outs to improve diagnosis and prognosis of CADASIL. We also
gained novel information on molecular changes associated with specific disease-causing mutations
which, at least partially, bring clarity into the broad phenotypic variation. In fact, our findings indicate that
some mutations in NOTCH3 result in suppression of the pathway, while others lead to hyperactivation of
Notch signaling. The objective of this U01 application is to further expand the information related to
clinical presentation, advance the characterization of disease-causing mutations and determine the chief
molecular alterations resulting from these mutations. Furthermore, we will validate animal models to
explore potential avenues for treatment. While a clinical trial is the eventual long-term goal of this
research, a comprehensive understanding of genotype-phenotype relationships with the support of our
colleagues at the NIH Clinical Center is the necessary first step towards this goal. Thus, here our
objective is to test the hypothesis that CADASIL is a broad pleotropic disease caused by both loss and
gain of function mutations in NOTCH3 which mechanistically explain the wide clinical outcomes
associated with vascular degeneration. To test this hypothesis, we present three specific aims: (1) To
develop a robust, multi-organ, longitudinal evaluation of disease progression in a large number of
patients and establish genotype-phenotype relationships; (2) To fully characterize the molecular outcome
of CADASIL mutations as gain or loss of function and associate them with specific molecular read-outs
(3) To explore recently generated animal models representative of both genotype spectra and validate
their utility as potential platforms for therapeutic exploration.
Terms: <Address><Adventitial Cell><Affect><Age><Agreement><Amentia><Animal Model><Animal Models and Related Studies><Apoplexy><Arterial Disorder><Arteries><Arteriopathy><Arteriosclerotic Dementia><Binswanger Disease><Binswanger Encephalopathy><Biopsy Sample><Biopsy Specimen><Bleeding><Blood Sample><Blood Vessels><Blood monocyte><Blood specimen><Body Tissues><Brain><Brain Nervous System><Brain Vascular Accident><Caliber><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cephalalgia><Cephalgia><Cephalodynia><Cerebral Stroke><Cerebral small vessel disease><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cerebrum><Characteristics><Chronic Progressive Subcortical Encephalopathy><Clinic><Clinical><Clinical Trials><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Collaborations><Cranial Pain><Data><Data Correlations><Dementia><Dermatologic biopsy><Development><Diagnosis><Disease><Disease Progression><Disorder><Disturbance in cognition><Drosophila Homolog of NOTCH 3><EXTMR><Encephalon><Endothelium><Evaluation><Evolution><Extramural><Extramural Activities><Failure><Generations><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genotype><Goals><Head Pain><Headache><Hemorrhage><Hereditary><Impaired cognition><Impairment><Inherited><Intracellular Communication and Signaling><Investigators><Ischemia><Knowledge><Lead><Leiomyocyte><Leukoencephalopathy><Life><Link><Marrow monocyte><Mice><Mice Mammals><Molecular><Murine><Mus><Mutation><NIH><NOTCH3><NOTCH3 gene><National Institutes of Health><Nature><Nerve Degeneration><Neurologic><Neurological><Neuron Degeneration><Non-Profit Organizations><Nonprofit Organizations><O element><O2 element><Organ><Outcome><Oxygen><Pathway interactions><Patients><Pb element><Pericapillary Cell><Pericytes><Perivascular Cell><Phenotype><Physicians><Physiologic><Physiological><Process><Prognosis><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Research><Research Personnel><Researchers><Retina><Rouget Cells><Scientist><Side><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Stroke><Subcortical Arteriosclerotic Encephalopathy><Subcortical Infarctions><Subcortical Infarcts><Subcortical Leukoencephalopathy><Symptoms><Testing><Therapeutic><Tissues><Translating><Tunica Media><United States National Institutes of Health><Variant><Variation><Vascular Dementia><Vascular Diseases><Vascular Disorder><Vascular Media><Vascular Medias><Vascular Smooth Muscle><ages><arteriole><autosome><biological signal transduction><blood loss><blood vessel disorder><brain attack><cerebral><cerebral small vessel disorder><cerebral vascular accident><cerebrovascular accident><clinical center><cognitive dysfunction><cognitive function><cognitive loss><cutaneous biopsy><deprivation><develop therapy><developmental><disease causing variant><disease-causing mutation><female patients><gain of function><gain of function mutation><genome mutation><gray matter><head ache><heavy metal Pb><heavy metal lead><human disease><iPS><iPSC><iPSCs><improved><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><insight><intervention development><loss of function><male><model of animal><monocyte><mouse model><murine model><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><notch><notch protein><notch receptors><novel><pathogenic variant><pathway><patients being female><patients being women><patients who are female><receptor><recruit><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skin biopsy><stroked><strokes><substantia grisea><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapy development><transcriptome profiling><transcriptome sequencing><transcriptomic profiling><transcriptomic sequencing><treatment development><vascular><vascular contributions to dementia><vascular dysfunction><vasculopathy><women patients>