The Role of Serine Protease Inhibitors in Nervous System Development

丝氨酸蛋白酶抑制剂在神经系统发育中的作用

• 批准号: 0344595
• 负责人: Haig Keshishian
• 金额: $ 40.25万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0344595&HistoricalAwards=false
• 关键词: Role; Serine; Protease; Inhibitors; Nervous

Abstract: In the developing nervous system many key proteins are modified or activated by proteolytic enzymes or proteases. These enzymes act both within the neuron as well as in the extracellular environment near growing processes and synapses. By cleaving key regulatory proteins the nervous system proteases influence the development of connections between nerve cells and their targets, and control the processing of secreted hormones and signaling molecules that are necessary for synapse function. The "serine proteases" are an important class of proteolytic enzymes in neurons. The serine proteases are widely conserved in evolution, and are important for both development as well as for changes associated with learning and memory. Understanding how these enzymes are controlled is the central goal of this project. Serine proteases are often regulated by a special class of proteins known as "serpins" (serine protease inhibitors). The serpins and serine proteases function as an interdependent system. In order to understand these proteins better Dr. Keshishian will examine their biological functions in a model genetic organism, Drosophila. In Drosophila Dr. Keshishian has already characterized the key serpins of the nervous system (Spn4), and has noted that Spn4 is expressed at connections between motoneurons and muscles. He has also discovered a second role for Spn4 in the enzymatic processing of precursor forms of secreted peptides and hormones. One variant of Spn4 binds to and regulates peptide processing serine proteases in vitro. When it is experimentally expressed in vivo the protein disrupts endogenous peptide hormone maturation, resulting in developmental abnormalities. A major goal will be to examine serpin functions at both developing neuromuscular connections, and in the processing of peptide hormones, and to test the effects of both its loss and overexpression. Studying Drosophila Spn4 will be of value in understanding how these regulatory molecules influence nervous system development and function in general.

翻译后摘要：在发育中的神经系统中，许多关键蛋白质被蛋白水解酶或蛋白酶修饰或激活。 这些酶在神经元内以及生长过程和突触附近的细胞外环境中起作用。 通过切割关键的调节蛋白，神经系统蛋白酶影响神经细胞与其靶点之间连接的发展，并控制突触功能所必需的分泌激素和信号分子的加工。“丝氨酸蛋白酶”是神经元中一类重要的蛋白水解酶。丝氨酸蛋白酶在进化中广泛保守，并且对于发育以及与学习和记忆相关的变化都很重要。了解这些酶是如何控制的是这个项目的中心目标。丝氨酸蛋白酶通常由称为“丝氨酸蛋白酶抑制剂”（丝氨酸蛋白酶抑制剂）的一类特殊蛋白质调节。丝氨酸蛋白酶抑制剂和丝氨酸蛋白酶作为一个相互依赖的系统发挥作用。为了更好地了解这些蛋白质，Keshishian博士将在一种模式遗传生物果蝇中研究它们的生物学功能。Keshishian博士已经在果蝇中描述了神经系统的关键丝氨酸蛋白酶抑制剂（Spn 4），并注意到Spn 4在运动神经元和肌肉之间的连接处表达。他还发现了Spn4在分泌肽和激素的前体形式的酶促加工中的第二个作用。Spn4的一种变体在体外结合并调节肽加工丝氨酸蛋白酶。 当它在体内实验表达时，该蛋白质破坏内源性肽激素成熟，导致发育异常。一个主要的目标将是检查丝氨酸蛋白酶抑制剂在神经肌肉连接发育和肽激素加工中的功能，并测试其缺失和过度表达的影响。研究果蝇Spn4将有助于了解这些调节分子如何影响神经系统的发育和功能。