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对细胞通信机制，几乎在所有多细胞生物中都可以找到，并允许发育细胞获得其专门的细胞类型（神经元，肌肉，消化，生殖等）。该系统具有许多组件，其中两个是该提案的主要重点。 这些是能够与Notch受体活性相互作用并影响Notch受体活性的Notch信号受体分子和锯齿状配体。 当这些分子在相邻的细胞上表达，导致形成不同细胞类型时，锯齿状配体可以激活受体。 当这些分子在同一细胞上共表达时，锯齿状也可以抑制受体，从而阻止此类细胞接收缺口信号并形成独特的细胞类型。该提案研究了锯齿状配体的特定区域和特性，这些区域负责抑制Notch受体，因此研究了控制细胞专业化的关键机理方面。这项工作利用锯齿分子的靶向分子遗传突变，随后在果蝇中表达这些突变形式，以研究其对Notch信号的影响。 预期结果将充分定义和表征锯齿状的区域，该区域赋予配体的抑制性能到缺口受体，并有可能定义对缺口激活必不可少的区域。 Notch系统组件的进化保守性质允许该研究结果非常广泛地适用于脊椎动物中同源分子。此外，这项研究将扩展对包括干细胞分化机制在内的多细胞动物中细胞分化控制的理解。这项研究将由本科研究人员进行，为这些学生提供强大的分子和遗传工具背景，用于随后的专业培训和发展。