Underlying Mechanisms of Vascular Disease

血管疾病的潜在机制

• 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
• 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

 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）：小血管疾病是以小动脉狭窄为特征的疾病，导致血液供应不平衡。这导致进行性慢性灌注不足，对受影响的器官系统和患者具有有害结果。受影响的血管床无法进行普通的经皮介入或血管移植。慢性低灌注和随后的缺血对许多治疗是难治的，长期结果不佳。遗传学评估的最新进展已经确定了几个导致脑血管小血管疾病的遗传变异。这些具有常见的临床表现，包括复发性中风、进行性白色物质变性和衰弱性痴呆。这些病理之间的联系是动脉图尼卡中膜的缺陷，其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特性的变化可导致损害顺应性的结构异常。U 01应用程序的目的是将从动物模型获得的发现扩展并验证到人类，以促进翻译。我们最近的发现表明，身份，以及维持vSMC的命运和收缩特性需要不断的信号从NOTCH 1和3。长期以来，人们已经认识到NOTCH 3的突变会导致一种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遗传性脑动脉病）。在这种疾病中，NOTCH 3突变导致图尼卡中膜的进行性变性，其首先表现在较小的动脉中，特别是在脑中的那些，但该疾病本质上是全身性的。有趣的是，我们的动物模型表明，虽然Notch 3中的失活突变是必要的，但该基因的功能丧失不足以引发疾病;此外，还需要Notch 1的减少。这些新信息为CADASIL的治疗干预提供了机会。虽然临床试验是本申请的最终目标，但使用NIH临床中心验证这些发现是测试以下假设的第一步：NOTCH 1信号传导的校正将改善CADASIL患者典型的图尼卡中膜的进行性变性。因此，在这里我们提出了三个具体的目的：（1）询问CADASIL患者中Notch信号传导的改变是否影响非脑血管床中的血管稳态，并为潜在的临床试验建立临床基线;（2）确定CADASIL患者是否表现出较低水平的Notch信号传导， NOTCH 1表达和疾病的临床阶段（或结果）是否显示与该途径的抑制激活相关，以及（3）确定NOTCH 1信号传导的调节是否可以转化为CADASIL患者的人类临床试验。 叙述：影响小血管的血管病理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经被确定，但有效的新治疗方法更难开发。本申请旨在探索一种用于这些疾病之一的新疗法：CADASIL，其导致偏头痛，痴呆和死亡。