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(申请人提供)：小血管疾病是以小动脉狭窄为特征的疾病，导致需求时血液供应不平衡。这会导致进行性的慢性低灌注率，对受影响的器官系统和患者都是有害的。受影响的血管床不能接受普通的经皮介入或血管移植。慢性低灌注率和随后的缺血对许多长期疗效不佳的治疗方法都是难治的。最近在遗传评估方面的进展已经确定了几个导致脑血管小血管疾病的基因变异。这些都有常见的临床表现，包括反复中风、进行性白质变性和衰弱痴呆症。这些病理之间的联系是动脉中膜的缺陷，主要由血管平滑肌细胞(VSMC)组成。这一肌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身份的改变可导致结构异常，从而损害顺应性。该U01应用程序的目标是将从动物模型获得的结果扩展并验证到人类身上，以促进翻译。我们最近的发现表明，vSMC的同一性以及vSMC命运和收缩特性的维持需要从Noch 1和Noch 3不断发出信号。长期以来，人们已经认识到Noch 3的突变会导致一种毁灭性的神经系统疾病：CADASIL(伴有皮质下梗塞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，缺口3突变导致中膜进行性退化，首先表现在较小的动脉，特别是大脑中的动脉，但这种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Notch3的失活突变是必要的，但该基因的功能丧失并不足以引发疾病；此外，Notch1的减少也是必要的。这一新信息为CADASIL的治疗干预提供了机会。虽然临床试验是这项应用的最终目标，但使用NIH临床中心对这些发现进行验证是验证NOTCH1信号正确将改善CADASIL患者典型的中膜进行性退化这一假设的第一步。因此，我们在这里提出了三个具体目标：(1)探讨CADASIL患者Notch信号的改变是否影响非脑血管床上的血管稳态，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 NOTCH1的表达以及疾病的临床分期(或结果)是否与该通路的激活抑制有关，以及(3)确定NOTCH1信号的调节是否可以转化为CADASIL患者的人类临床试验。 简介：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经被识别出来，但有效的新疗法一直很难开发。这项申请旨在探索一种治疗其中一种疾病的新方法：CADASIL，它会导致迁徙、痴呆症和死亡。