Underlying Mechanisms in CADASIL

脑微血管缺血性疾病是白质脑病的常见原因，导致认知 损伤、痴呆症和中风。伴皮质下的常染色体显性遗传性脑动脉病 脑梗塞和白质脑病)是脑部小血管最常见的孟德尔病因 疾病。二十多年前，在受体中发现了致病的CADASIL突变 NOTCH3.这些突变导致血管平滑肌细胞进行性退化。 小动脉。虽然CADASIL具有全身性，但与CADASIL相关的临床缺陷主要表现在 脑部作为一种血管疾病，导致多灶性脑缺血伴进行性认知功能下降。尽管 它对患者的破坏性影响，我们对这种疾病的了解是有限的，限制了针对性 治疗策略。进步的一个主要障碍是疾病的广泛变异性。 关于CADASIL是由于功能的增加或丧失而导致的表现和缺乏共识 NOTCH3信令。 通过与NIH临床中心的合作，我们已经在以下方面取得了重大进展 定义更广泛的临床读数以改善CADASIL的诊断和预后。我们也 获得了与特定致病突变相关的分子变化的新信息 这至少部分地为广泛的表型变异带来了清晰度。事实上，我们的发现表明 NOTCH3中的一些突变导致该通路的抑制，而另一些突变则导致该通路的过度激活 凹槽信号。本U01申请的目的是进一步扩展与以下内容相关的信息 临床表现，推进致病突变的特征并确定主要 由这些突变引起的分子变化。此外，我们将验证动物模型以 探索潜在的治疗途径。虽然临床试验是这项研究的最终长期目标 研究，在我们的支持下，对基因型-表型关系的全面理解 NIH临床中心的同事是迈向这一目标的必要的第一步。因此，在这里我们的 目的是验证CADASIL是一种广泛的多发性疾病的假设，这种疾病是由丢失和 NOTCH3功能突变的获得，从机制上解释了广泛的临床结果 与血管退化有关。为了验证这一假设，我们提出了三个具体目标：(1) 开发一种强大的、多器官的、纵向的对疾病进展的评估 患者和建立基因-表型关系；(2)充分表征分子结果 CADASIL突变作为功能的获得或丧失，并将它们与特定的分子读出相关联 (3)探索最近产生的代表两种基因谱系的动物模型，并验证 它们作为潜在的治疗探索平台的效用。

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.