The Role of Serine Protease Inhibitors in Nervous System Development

摘要：在发育中的神经系统中，许多关键蛋白被蛋白水解酶或蛋白酶修饰或激活。这些酶既在神经元内起作用，也在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过程中广泛保守，对发育以及与学习和记忆相关的变化都很重要。了解这些酶是如何被控制的是这个项目的中心目标。丝氨酸蛋白酶通常由一类称为“丝氨酸蛋白酶抑制剂”的特殊蛋白质调节。丝氨酸蛋白酶和丝氨酸蛋白酶是一个相互依赖的系统。为了更好地了解这些蛋白质，Keshishian博士将在一种遗传生物模型果蝇中研究它们的生物学功能。在果蝇中，Keshishian博士已经描述了神经系统的关键蛇形蛋白（Spn4），并注意到Spn4在运动神经元和肌肉之间的连接中表达。他还发现了Spn4在分泌肽和激素的前体形式的酶处理中的第二个作用。Spn4的一个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，该蛋白会破坏内源性肽激素的成熟，导致发育异常。一个主要的目标将是检查serpin在发展神经肌肉连接和肽激素加工中的功能，并测试其丢失和过度表达的影响。研究果蝇Spn4将有助于理解这些调节分子如何影响神经系统的发育和功能。

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.