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Underlying Mechanisms in CADASIL

CADASIL 的底层机制

基本信息

批准号：
10394276
负责人：
Manfred Boehm
金额：
$ 66.93万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10394276
关键词：
Address Affect Age Agreement Animal Model Arterial Disorder Arteries Biopsy Biopsy Specimen Blood Vessels Blood specimen Brain Caliber Cells Cerebral small vessel disease Cerebrum Characteristics Clinic Clinical Clinical Trials Collaborations Data Dementia Development Diagnosis Disease Disease Progression Endothelium Evaluation Evolution Extramural Activities Failure Female Generations Genetic Genotype Goals Headache Impaired cognition Impairment Inherited Ischemia Knowledge Lead Leukoencephalopathy Life Link Molecular Mus Mutation NOTCH3 gene Nature Nerve Degeneration Neurologic Nonprofit Organizations Ophthalmology Organ Outcome Oxygen Pathway interactions Patients Pericytes Phenotype Physicians Physiological Process Prognosis Research Research Personnel Retina Scientist Side Signal Transduction Skin Smooth Muscle Myocytes Stroke Subcortical Infarctions Subcortical Leukoencephalopathy Symptoms Testing Therapeutic Tissues Translating Tunica Media United States National Institutes of Health Variant Vascular Dementia Vascular Diseases Vascular Smooth Muscle arteriole base clinical center cognitive function deprivation disease-causing mutation gain of function gain of function mutation gray matter human disease improved induced pluripotent stem cell insight loss of function male monocyte mouse model notch protein novel receptor recruit single-cell RNA sequencing targeted treatment therapy development transcriptome sequencing transcriptomics

项目摘要

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.

脑微血管缺血性疾病是脑白质病的常见病因，导致认知障碍