RUI: Characterization of Notch Cis-Inhibitory Sequences in the Serrate Ligand of Drosophila Melanogaster

RUI：果蝇锯齿状配体中缺口顺式抑制序列的表征

• 批准号: 1121214
• 负责人: Robert Fleming
• 金额: $ 31.67万
• 依托单位: Trinity College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1121214&HistoricalAwards=false
• 关键词: RUI; Characterization; Notch; Cis; Inhibitory

The Notch signaling system is a cell-to-cell communication mechanism that is found in virtually all multicellular organisms and allows developing cells to acquire their specialized cellular types (neuronal, muscular, digestive, reproductive, etc.). This system has many components, two of which are the main focus of this proposal. These are the Notch signal receptor molecule and the Serrate ligand that is capable of interacting with and affecting Notch receptor activity. The Serrate ligand can activate the receptor when these molecules are expressed on adjacent cells leading to the formation of different cell types. Serrate can also inhibit the receptor when these molecules are co-expressed on the same cell, preventing such cells from receiving a Notch signal and forming distinctive cellular types. This proposal investigates the specific regions and properties of the Serrate ligand that are responsible for inhibiting the Notch receptor hence investigating a crucial mechanistic aspect for controlling cellular specialization. The work utilizes targeted molecular-genetic mutation of the Serrate molecule with subsequent expression of these mutated forms in the fruit fly to investigate their effects on Notch signaling. The outcomes are expected to fully define and characterize the regions of Serrate that confer the inhibitory property of the ligand onto the Notch receptor and potentially define regions essential for Notch activation. The evolutionarily conserved nature of Notch system components allows for very broad applicability of the findings of this study to the homologous molecules in vertebrates. Further, this study will extend the understanding of cellular differentiation control in multicellular animals including stem cell differentiation mechanisms. The study will be conducted by undergraduate researchers providing these students with a strong background in molecular and genetic tools for subsequent professional training and development.

Notch 信号系统是一种细胞间通讯机制，几乎存在于所有多细胞生物体中，并允许发育中的细胞获得其特殊的细胞类型（神经元、肌肉、消化、生殖等）。该系统有许多组件，其中两个是本提案的主要焦点。 这些是Notch信号受体分子和能够与Notch受体活性相互作用并影响Notch受体活性的锯齿配体。 当这些分子在相邻细胞上表达时，锯齿配体可以激活受体，从而形成不同的细胞类型。 当这些分子在同一细胞上共表达时，Serrate 还可以抑制受体，防止这些细胞接收 Notch 信号并形成独特的细胞类型。该提案研究了负责抑制 Notch 受体的锯齿状配体的特定区域和特性，从而研究了控制细胞特化的关键机制。这项工作利用 Serrate 分子的靶向分子遗传突变以及随后在果蝇中表达这些突变形式来研究它们对 Notch 信号传导的影响。 预计结果将完全定义和表征锯齿状区域，这些区域将配体的抑制特性赋予Notch受体，并可能定义Notch激活所必需的区域。 Notch 系统组件的进化保守性使得本研究的结果可以非常广泛地应用于脊椎动物的同源分子。此外，这项研究将扩展对多细胞动物细胞分化控制（包括干细胞分化机制）的理解。该研究将由本科生研究人员进行，为这些学生提供分子和遗传工具方面的强大背景，以便进行后续的专业培训和发展。