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Underlying Mechanisms of Vascular Disease

血管疾病的潜在机制

基本信息

批准号：
9288213
负责人：
Manfred Boehm
金额：
$ 54.49万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-06 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9288213
关键词：
Adult Affect Agonist Alagille Syndrome Animal Model Antibodies Arteries Bioinformatics Blood Vessels Brain Brain Diseases CADASIL Cells Cessation of life Chronic Clinical Clinical Treatment Clinical Trials Cognitive deficits Complement DNA Sequence Alteration Data Defect Dementia Depressed mood Development Diagnosis Disease Disease Progression Disease model Evaluation Exhibits Exons Extramural Activities Feedback Financial compensation Future Genes Genetic Genetic Transcription Goals Heart Abnormalities Hepatic Homeostasis Human Image Impairment Individual Inherited Intervention Ischemia Knock-in Knowledge Laboratories Lead Link Longevity Maintenance Microvascular Dysfunction Modeling Molecular Mus Muscle Muscle Cells Mutate Mutation NOTCH1 gene NOTCH3 gene National Heart, Lung, and Blood Institute Natural History Nature Neurologic Onset of illness Ophthalmic examination and evaluation Outcome Pathology Pathway interactions Patients Population Property Public Health Reagent Recurrence Refractory Repression Research Research Personnel Resources Signal Transduction Skin Smooth Muscle Smooth Muscle Myocytes Snow Statistical Data Interpretation Stroke Symptoms Technology Testing Therapeutic Intervention Translating Translational Research Translations Tunica Media United States National Institutes of Health Validation Variant Vascular Dementia Vascular Diseases Vascular Graft Vascular Smooth Muscle Vascular blood supply base body system cerebrovascular experimental study gene function genetic variant hypoperfusion induced pluripotent stem cell loss of function model development mouse model nervous system disorder notch protein novel therapeutics outcome forecast patient population vascular bed white matter

项目摘要

DESCRIPTION (provided by applicant): Small vessel diseases are conditions characterized by the narrowing of small arteries leading to an imbalance of blood supply upon demand. This results in a progressive chronic hypoperfusion with detrimental outcomes for the affected organ system and for the patient. The affected vascular beds are not accessible to common percutaneous intervention or vascular grafting. Chronic hypoperfusion and subsequent ischemia are refractory to many therapies with poor long-term outcome. Recent advances in genetic evaluation have identified several genetic variants causing cerebrovascular small vessel diseases. These have common clinical presentation including recurrent strokes, progressive white matter degeneration, and debilitating dementia. The link between these pathologies are defects in the tunica media of arteries, which is composed mainly of vascular smooth muscle cells (vSMC). The functional integrity of this muscular layer is essential for its function, thus alterations in the contractile properties or changes in the identity of vSMC can result in structurl anomalies that impair compliance. The objective of this U01 application is to expand and validate findings obtained from animal models into humans to promote translation. Our recent discoveries indicate that the identity, as well as the maintenance of vSMC fate and contractile properties requires constant signaling from NOTCH 1 and 3. It has been long recognized that mutations in NOTCH 3 result in a devastating neurological disease: CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). In this disease, NOTCH 3 mutations result in progressive degeneration of the tunica media that is first manifested in smaller arteries, particularly those in the brain but the disease is systemic in nature. Interestingly, our animal models indicate that while inactivating mutations in Notch3 are necessary, loss of function of this gene is not sufficient to trigger the disease; in addition reduction of Notch1 is also required. This new information provides the opportunity for therapeutic intervention in the treatment of CADASIL. While a clinical trial is the eventual goal o this application, validation of these findings using the NIH Clinical Center is a first step to tes the hypothesis that correction in NOTCH1 signaling will ameliorate the progressive degeneration of the tunica media typical of CADASIL patients. Thus, here we present three specific aims: (1) To inquire whether alterations of Notch signaling in CADASIL patients affect vascular homeostasis in non-cerebral vascular beds and establish a clinical baseline for a potential clinical trial; (2) To determine whether individuals with CADASIL exhibit lower levels of NOTCH1 expression and whether the clinical stage of the disease (or outcome) shows correlation with depressed activation of this pathway and (3) To determine if modulation of NOTCH1 signaling could be translated to a human clinical trial in CADASIL patients. Narrative: Vascular pathologies affecting small vessels underlie many hereditary multi-organ diseases. While most of the underlying genetic mutations have been identified, effective new treatments have been more difficult to develop. This application proposes to explore a novel therapy for one of those diseases: CADASIL that causes migranes, dementia and death.