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: 7211118
• 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/7211118
• 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 目的：本提案的目的是阐明调节 NRAGE 在神经发育中促凋亡作用的分子机制，并在未来利用该信息设计 NRAGE 功能调节剂，作为 caspase 活性和细胞活力的间接调节剂。假设：该提议的基础是 NRAGE 作为导致 p38MAPK 和 caspase 激活的非经典骨形态发生蛋白 (BMP) 信号通路不可或缺的组成部分。这可能与介导接受类维生素A治疗的人类髓母细胞瘤患者的肿瘤死亡相同。新的初步证据表明，NRAGE 独特的六肽重复对于介导皮质祖细胞凋亡（髓母细胞瘤形成的基础细胞）至关重要。此外，该区域还结合凋亡蛋白 Xiap 的抑制剂。理所当然，识别和改变这种相互作用将在调节 caspase 激活和细胞活力方面具有巨大潜力。为了完善 NRAGE 在神经祖细胞凋亡中的作用，我们提出以下两个具体目标： I. 阐明 NRAGE 在非经典 BMP 信号级联中的作用，导致 BMP 诱导的 p38MAPK 激活和神经祖细胞凋亡。对非经典 BMP 信号通路进行分子剖析，以确定 NRAGE 在神经祖细胞凋亡中的作用，重点关注调节非经典 BMP 信号传导所需的 TAK-TAB-NRAGE-XIAP 复合物的形成。二.确定经典 BMP 信号在调节 NRAGE 蛋白表达中的作用。由于神经祖细胞中 Smad4 基因的条件突变，经典 BMP 信号传导被废除的小鼠中，NRAGE 表达和 BMP 介导的细胞凋亡将受到挑战。我们建议拟议的研究将阐明 NRAGE 的功能，从而对神经科学界具有广泛的意义。此外，NRAGE：Xiap相互作用的识别和操纵可以增强NRAGE作为操纵caspase活性的治疗靶点的效用，以对抗多种人类疾病，特别是髓母细胞瘤。