Underlying Mechanisms in CADASIL

脑微血管缺血性疾病是白质脑病的常见原因，导致认知功能障碍， 损伤痴呆和中风CADASIL（伴有皮质下的常染色体显性遗传性脑动脉病） 脑梗死和白质脑病）是脑小血管病最常见的孟德尔原因。 疾病二十多年前，在受体中发现了导致疾病的CADASIL突变， NOTCH 3.这些突变导致血管平滑肌细胞的进行性变性， 小动脉虽然本质上是全身性的，但与CADASIL相关的临床缺陷主要表现在 脑血管疾病，导致多灶性缺血，认知能力逐渐下降。尽管 它对患者的破坏性影响，我们对疾病的了解有限，限制了针对性 治疗策略进展的一个主要障碍是疾病的广泛变异性 对于CADASIL是否由以下因素引起的功能获得或丧失， NOTCH 3信号。 通过与NIH临床中心的合作，我们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 这至少部分地使广泛的表型变异变得清晰。事实上，我们的研究结果表明， NOTCH 3中的一些突变导致该途径的抑制，而其他突变则导致该途径的过度激活。 陷波信号。本U 01应用程序的目标是进一步扩展与以下内容相关的信息 临床表现，推进致病突变的表征，并确定主要的 由这些突变引起的分子变化。此外，我们将验证动物模型， 探索潜在的治疗途径。虽然临床试验是最终的长期目标， 研究，在我们的支持下全面了解基因型-表型关系 与NIH临床中心的同事合作是实现这一目标的必要的第一步。因此，这里我们的 目的是检验CADASIL是一种广泛的多效性疾病的假设， 获得NOTCH 3的功能突变，这在机制上解释了广泛的临床结局 与血管变性有关为了验证这一假设，我们提出了三个具体目标：（1） 开发一个强大的，多器官，纵向评估疾病进展，在大量的 患者，并建立基因型-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，并将其与特定的分子读数相关联 (3)探索最近生成的代表两种基因型谱的动物模型， 它们作为治疗探索的潜在平台的效用。

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.