Notch Functions in the Adult Nervous System

成人神经系统中的Notch功能

• 批准号: 7654805
• 负责人: Anne Church Hart
• 金额: $ 5.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7654805
• 关键词: Address; Adult; Alagille Syndrome; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Behavior; Binding Sites; Bioinformatics; Biological Models; CADASIL; Caenorhabditis elegans; Candidate Disease Gene; Cell Proliferation; Cells; Defect; Dementia; Development; Diagnosis; Disease; Down Syndrome; Drosophila genus; Gene Targeting; Genes; Genetic; Genetic Screening; Genetic Techniques; Homologous Gene; Human; Inborn Genetic Diseases; Incidence; Knowledge; Ligands; Locomotion; Memory; Molecular; Molecular Genetics; Molecular Target; Mus; Mutation; Nervous system structure; Neurons; Notch Signaling Pathway; Pathway Analysis; Pathway interactions; Patients; Play; Proteins; Publishing; Reagent; Regulation; Role; Signal Transduction; Site; Stem cells; Stroke; System; Techniques; Validation; base; effective therapy; genetic analysis; genome wide association study; mature animal; memory retention; neuronal circuitry; notch protein; public health relevance; response; sensory stimulus; tool

DESCRIPTION (provided by applicant): Notch signaling plays well described roles in developmental cell fate decisions, in the regulation of stem cell proliferation and in numerous diseases. However, Notch signaling is also critical for the function of adult neurons. Notch plays a role in memory retention in mice and Drosophila, yet the targets of Notch signaling in neurons are unclear. We have demonstrated that the C. elegans lin-12 Notch receptor acts in adult animals to modulate behavior. In the studies proposed here, we will identify the molecular pathways by which Notch signaling alters neuronal function and behavior using the powerful genetic techniques available in C. elegans. In a pilot screen, we identified five genes expressed in the nervous system that are likely direct targets of Notch. All five genes encode proteins that are likely critical for Notch signaling in vertebrate neurons as well. In this proposal, we address the mechanisms and pathways by which these Notch target genes act in the adult nervous system to regulate neuronal activity and behavior. PUBLIC HEALTH RELEVANCE: Notch signaling is critical for normal function of the human nervous system. Mutations in Notch3 and Jagged1 cause CADASIL and Alagille syndromes, respectively. These are dominantly inherited disorders associated with stroke and dementia. Combined, their incidence is at least 1 in 50,000, although CADASIL is likely under-diagnosed. Recent evidence also suggests that Notch signaling is up-regulated in Down's syndrome patients. Interestingly, Notch and amyloid precursor proteins directly interact suggesting that Notch signaling may be important in the memory defects associated with Alzheimer's disease. There is no effective treatment for these disorders. Given the conservation across species of Notch regulatory mechanisms and targets, we anticipate that identifying the targets of Notch signaling in C. elegans will reveal critical targets of Notch modulation in humans that are relevant in both normal and pathological conditions.

描述（由申请人提供）：Notch信号传导在发育细胞命运决定、干细胞增殖调节和许多疾病中发挥了充分描述的作用。然而，Notch信号传导对成年神经元的功能也至关重要。Notch在小鼠和果蝇的记忆保持中发挥作用，但神经元中Notch信号传导的靶点尚不清楚。我们证明了C.线虫lin-12 Notch受体在成年动物中起调节行为的作用。在这里提出的研究中，我们将确定Notch信号改变神经元功能和行为的分子途径，使用强大的遗传技术在C。优美的在初步筛选中，我们确定了五个在神经系统中表达的基因，它们可能是Notch的直接靶点。所有五个基因编码的蛋白质可能对脊椎动物神经元中的Notch信号传导也至关重要。在这项提案中，我们解决了这些Notch靶基因在成人神经系统中发挥作用以调节神经元活动和行为的机制和途径。 Notch信号对人类神经系统的正常功能至关重要。Notch 3和Jagged 1的突变分别导致CADASIL和Alagille综合征。这些是与中风和痴呆相关的显性遗传性疾病。合并后，其发病率至少为1/50，000，尽管CADASIL可能诊断不足。最近的证据还表明，Notch信号在唐氏综合征患者中上调。有趣的是，Notch和淀粉样前体蛋白直接相互作用，表明Notch信号可能在与阿尔茨海默病相关的记忆缺陷中很重要。对于这些疾病没有有效的治疗方法。考虑到Notch调控机制和靶点在物种间的保守性，我们预计在C. elegans将揭示人类Notch调节的关键靶点，这些靶点在正常和病理条件下都是相关的。