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.

描述（由申请人提供）：小血管疾病的特征是小动脉狭窄，导致血液供应不平衡，从而导致进行性慢性灌注不足，从而对受影响的器官系统和受影响的患者产生不健康的结果。血管床无法通过常见的经皮介入或血管移植来治疗，并且随后的缺血对于许多长期结果不佳的治疗方法来说是难以治愈的。这些疾病具有常见的临床表现，包括复发性中风、进行性白质变性和衰弱性痴呆。这些病变之间的联系是动脉中膜的缺陷，动脉中膜主要由血管平滑肌细胞 (vSMC) 组成。该肌肉层的功能完整性对其功能至关重要，因此收缩特性的改变或 vSMC 特性的变化可能会导致结构异常，从而损害顺应性。我们最近的发现表明，vSMC 命运和收缩特性的身份以及维持需要来自 NOTCH 1 和 3 的持续信号传导。 NOTCH 3 突变会导致毁灭性的神经系统疾病：CADASIL（伴有皮质下梗死和白质脑病的常染色体显性脑动脉病）。在这种疾病中，NOTCH 3 突变会导致神经系统进行性变性。中膜首先出现在较小的动脉中，特别是大脑中的动脉，但该疾病本质上是全身性的，此外，这一新信息也为 CADASIL 的治疗干预提供了机会。临床试验是本申请的最终目标，使用 NIH 临床中心验证这些发现是第一步验证了 NOTCH1 信号传导的纠正将改善 CADASIL 患者典型的中膜进行性退化的假设，因此，我们在这里提出三个具体目标：(1) 探究 CADASIL 患者中 Notch 信号传导的改变是否影响非血管内稳态。 (2) 确定患有 CADASIL 的个体是否表现出较低水平的 NOTCH1 表达以及疾病的临床阶段（或结果）是否与该通路的激活抑制相关，以及 (3) 确定 NOTCH1 信号传导的调节是否可以转化为 CADASIL 患者的人体临床试验。叙述：影响小血管的血管病变是许多遗传性多器官疾病的基础，虽然大多数潜在的基因突变已被识别，但有效的新疗法更难开发，该申请旨在探索一种针对这些疾病的新疗法： CADASIL 会导致偏头痛、痴呆和死亡。