NRAGE: A mediator of p38 map kinase and caspase activity in the CNS.

NRAGE：CNS 中 p38 图谱激酶和 caspase 活性的介质。

• 批准号: 7340446
• 负责人: JOSEPH M VERDI
• 金额: $ 33.56万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340446
• 关键词: Affinity; Apoptosis; Apoptotic; Binding; Binding Proteins; Bone Morphogenetic Proteins; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; Childhood Medulloblastomas; Clinical; Communities; Complex; Dissection; Eating; Event; Functional disorder; Future; Genes; Homeostasis; Human; Knowledge; Laboratories; MAPK14 gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Mediating; Mediator of activation protein; Molecular; Mus; Mutation; NGFR Protein; Nerve Degeneration; Nerve Growth Factor Receptors; Nerve Growth Factors; Neurodegenerative Disorders; Neuroepithelial, Perineurial, and Schwann Cell Neoplasm; Neurosciences; Normal tissue morphology; Patients; Phosphotransferases; Process; Prosencephalon; Protein Family; Proteins; Retinoids; Role; Signal Pathway; Signal Transduction; Ventricular; X-linked IAP; base; caspase-3; design; human MAPK14 protein; human disease; inhibitor-of-apoptosis protein; killings; medulloblastoma; member; mitogen-activated protein kinase p38; neoplastic cell; neurodevelopment; progenitor; protein expression; protein function; relating to nervous system; therapeutic target; tumor

Objective: The objective of this proposal is to clarify the molecular mechanisms that regulate the pro- apoptotic effects of NRAGE in neural development, and to utilize this information in the future to design modulators of NRAGE function as indirect regulators of caspase activity and cell viability. Hypothesis: The basis of this proposal is that NRAGE functions as an indispensable component of the non-canonical Bone Morphogenetic Protein (BMP)-signaling pathway leading to p38MAPK and caspase activation. This may be the same that mediates the tumor death of human medulloblastoma patients undergoing retinoid therapy. New preliminary evidence demonstrates that the unique hexapeptide repeat of NRAGE is essential in mediating cortical progenitor apoptosis, the cells that underlie medulloblastoma formation. In addition this region binds the inhibitor of apoptosis protein Xiap. It stands to reason that discerning and altering this interaction will have great potential in regulating caspase activation and cell viability. In order to refine the role of NRAGE in neural progenitor apoptosis, we propose the following two Specific Aims: I. Elucidate the role of NRAGE in the non-canonical BMP signaling cascade resulting in BMP- induced p38MAPK activation and apoptosis of neural progenitors. A molecular dissection of the non- canonical BMP-signaling pathway will be undertaken to ascertain the role of NRAGE in neural progenitor apoptosis with emphasis on the formation of the TAK-TAB-NRAGE-XIAP complex needed to regulate non-canonical BMP signaling. II. Determine the role of canonical BMP signaling in regulating NRAGE protein expression. NRAGE expression and BMP-mediated apoptosis will be challenged in mice with abrogated canonical BMP signaling due to a conditional mutation in the Smad4 gene in neural progenitors. We suggest that the proposed studies will clarify the function of NRAGE, and thus will have broad significance to the neuroscience community. Also, the identification and manipulation of NRAGE: Xiap interactions may enhance the utility of NRAGE as a therapeutic target in manipulating caspase activity to combat a variety of human diseases, especially medulloblastoma.

目的：本研究的目的是阐明调节促甲状腺激素分泌的分子机制， 神经发育中的细胞凋亡作用，并利用这一信息在未来的设计 NATRA的调节剂作为半胱天冬酶活性和细胞活力的间接调节剂发挥作用。 假设：这一建议的基础是，若虫作为一个不可或缺的组成部分， 非经典骨形态发生蛋白（BMP）信号通路导致p38 MAPK和caspase activation.这可能与介导人髓母细胞瘤患者的肿瘤死亡相同 正在接受维甲酸治疗新的初步证据表明，独特的六肽 重复的神经元是必不可少的介导皮质祖细胞凋亡，细胞的基础， 髓母细胞瘤形成。此外，该区域结合凋亡蛋白的抑制剂Xip。它 有理由认为，识别和改变这种相互作用将有很大的潜力， 半胱天冬酶活化和细胞活力。为了进一步明确Neptin在神经前体细胞凋亡中的作用， 我们提出以下两个具体目标： I.阐明NCLs在非经典BMP信号级联中的作用，导致BMP- 诱导p38 MAPK活化和神经前体细胞凋亡。从分子角度剖析非- 将进行典型的BMP信号传导途径以确定NMPs在神经细胞中的作用。 祖细胞凋亡，重点是TAK-TAB-NRAGE-XIAP复合物的形成， 调节非典型BMP信号传导。 二.确定经典BMP信号在调节NERK蛋白表达中的作用。 在小鼠中，NMPs表达和BMP介导的细胞凋亡将受到挑战， 神经祖细胞中Smad 4基因条件突变引起的BMP信号传导 我们认为，拟议的研究将阐明若虫的功能，从而将有广泛的 对神经科学界的意义。此外，识别和操纵的Ningdom：Xip 相互作用可以增强Neptin作为操纵caspase的治疗靶点的效用， 抗多种人类疾病的活性，尤其是髓母细胞瘤。