NOTCH SIGNALING IN MAMMALIAN CELLS

描述：Notch/LIN-12/GLP-1跨膜家族成员 受体被认为在发育中起着核心作用，它通过调节 无脊椎动物的细胞命运决定。申请者已分离出几个 编码大鼠Notch受体和Notch配体的基因，并已被 研究它们的表达和功能以探讨其分子机制。 哺乳动物发育过程中的缺口信号。缺口与以下内容关联 恶性肿瘤，表明在治疗过程中维持一种不确定的状态 正常发育，而Notch也参与了人类的中风障碍 和痴呆症(CADASIL和阿尔茨海默病)，表明在 发展也是如此。建议的实验是基于申请者的 和是合乎逻辑的扩展，旨在回答许多 关于Notch函数的基本问题。他们将确定诺奇是否 作为二聚体或单体，如果Notch的配体激活涉及 配体二聚化。他们还将探索Notch细胞表面是如何 表达受调控并研究Notch被切割的假说 并在配体结合后转运到核内。与之形成鲜明对比的是 关于无脊椎动物系统的报道，他们使 令人惊讶的是，哺乳动物的配体在它们的 激活不同Notch受体的能力。基于这些 通过观察，他们设计了实验来识别存在的序列 在解释观察到的配体的配体和受体中 专一性。此外，他们还将探索生产和使用 用于研究Notch信号转导的Notch配体的可溶性形式。他们发现 Notch信号导致CBF1依赖的和 CBF1-非依赖通路。初步数据显示， CBF1依赖的通路正向调节Notch的表达。他们 将研究这种积极反馈背后的分子机制 系统。他们还将研究相互发送信号的可能性。 配体-受体相互作用后表达配体的细胞。同舟共济 这项资助中提议的实验将提供关于 Notch-配体相互作用的结构/功能要求 扩展我们目前对哺乳动物Notch信号的理解。

DESCRIPTION: Members of the Notch/LIN-12/GLP-1 family of transmembrane receptors are believed to play a central role in development by regulating cell-fate decisions in invertebrates. The applicant has isolated several genes encoding Notch receptors and Notch ligands from rat, and has been studying their expression and function to address the molecular mechanism of Notch signaling during mammalian development. Notch is associated with malignancies, suggesting a role for maintaining an undetermined state during normal development, and Notch is also involved in human disorders of stroke and dementia (CADASIL and Alzheimer's disease), suggesting a role outside of development as well. Experiments proposed are based on the applicant's previous findings, and are logical extensions designed to answer a number of basic questions concerning Notch function. They will determine if Notch functions as a dimer or monomer, and if ligand activation of Notch involves ligand dimerization. They also will explore how Notch cell surface expression is regulated and investigate the hypothesis that Notch is cleaved and transported to the nucleus following ligand binding. In contrast to what has been reported for the invertebrate systems, they made the surprising observation that the mammalian ligands are not equal in their ability to activate the different Notch receptors. Based on these observations, they have designed experiments to identify sequences present in the ligands and receptors that account for the observed ligand specificity. In addition, they will explore the production and use of soluble forms of Notch ligands to study Notch signaling. They found that Notch signaling leads to activation of both CBF1-dependent and CBF1-independent pathways. Preliminary data indicate that the CBF1-dependent pathway positively regulates the expression of Notch. They will investigate the molecular mechanisms underlying this positive feedback system. They will also examine the possibility of reciprocal signaling in the ligand-expressing cell following ligand-receptor interactions. Together the experiments proposed in this grant will provide new information on the structure/function requirements of Notch-ligand interactions and thereby extend our present understanding of mammalian Notch signaling.