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: 0641915
• 负责人: Haig Keshishian
• 金额: $ 43万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0641915&HistoricalAwards=false
• 关键词: Role; Serine; Protease; Inhibitors; Nervous

Nerve cells communicate with each other at specialized structures known as synapses. At the synapse cells are anchored to each other by specialized proteins that function like glues. During development it is necessary to unstick or modify these adhesive proteins, so that nerve branches can grow and new connections can be made. Similar changes occur at some synapses in the brain when new memories are formed.The adhesive proteins are broken down by enzymes known as proteases. The proteases are made by nerve cells and are released at the synapse. The released proteases do not degrade synaptic proteins in an uncontrolled fashion. Instead, they encounter other proteins known as "serpins", which inhibit the proteases. Thus, in areas where serpin levels are high, the protease activity is reduced. Serpins are made by many kinds of nerve cell, both in mammals and in invertebrates. For example, the most common serpin of the human brain (Neuroserpin) is closely related to the serpin found in the brain of the fruit fly Drosophila, known as Spn4. In this proposal the PI will examine the synapses made between nerve cells and muscles in Drosophila. Spn4 is found at these synapses, where we hypothesize that it inhibits one or more proteases involved in the normal development of the synapse.The role that the Spn4 plays in both the development and function of nerve-muscle synapses will be examined in situations where the amount of the protein is either increased or reduced during development. This project will examine how nervous system activity influences the amount or function of Spn4 using various genetic mutations. Finally, the PI will identify the proteases that are inhibited by Spn4. Broader Impacts of Proposed Activity: Education and outreach. The investigator has extensive experience training undergraduates, graduate students, and postdoctoral fellows, including members from underrepresented minority groups (including one graduate student in this proposal). He encourages undergraduate research, including publication of papers supported by the previous NSF funding (1 undergraduate first author, 1 coauthor). The project will support the continued training of students in the areas of cellular neurobiology, neural development, and genetics, preparing them for advanced scientific careers. Research community: Many of the reagents and transgenic lines developed in the lab are of widespread utility, and are freely available to researchers, furthering scientific inquiry. Finally, fundamental knowledge about the molecular and cellular mechanisms governing of synaptic development and plasticity provides a firm foundation for developing future neurobiological applications of general benefit to society.

神经细胞通过称为突触的特殊结构相互通信。在突触处，细胞通过特殊的蛋白质彼此锚定，其功能就像胶水一样。 在发育过程中，有必要解开或修改这些粘附蛋白，以便神经分支可以生长并可以建立新的连接。当新的记忆形成时，大脑中的一些突触也会发生类似的变化。粘附蛋白被称为蛋白酶的酶分解。蛋白酶由神经细胞产生并在突触处释放。释放的蛋白酶不会以不受控制的方式降解突触蛋白。相反，它们会遇到其他称为“丝氨酸蛋白酶抑制剂”的蛋白质，这种蛋白质会抑制蛋白酶。因此，在丝氨酸蛋白酶抑制剂水平较高的区域，蛋白酶活性降低。丝氨酸蛋白酶抑制剂由多种神经细胞产生，包括哺乳动物和无脊椎动物。例如，人脑中最常见的丝氨酸蛋白酶抑制剂（Neuroserpin）与果蝇大脑中发现的丝氨酸蛋白酶抑制剂（称为 Spn4）密切相关。在这项提案中，PI 将检查果蝇神经细胞和肌肉之间形成的突触。 Spn4 在这些突触中被发现，我们假设它抑制一种或多种参与突触正常发育的蛋白酶。 Spn4 在神经肌肉突触的发育和功能中所起的作用将在发育过程中蛋白质含量增加或减少的情况下进行检查。 该项目将利用各种基因突变来研究神经系统活动如何影响 Spn4 的数量或功能。最后，PI 将识别出 Spn4 抑制的蛋白酶。拟议活动的更广泛影响：教育和推广。该研究者在培训本科生、研究生和博士后研究员方面拥有丰富的经验，其中包括来自代表性不足的少数群体的成员（包括本提案中的一名研究生）。他鼓励本科生研究，包括发表由之前的 NSF 资助支持的论文（1 名本科生第一作者，1 名共同作者）。该项目将支持学生在细胞神经生物学、神经发育和遗传学领域的持续培训，为他们进入高级科学职业做好准备。研究界：实验室开发的许多试剂和转基因品系具有广泛的用途，并且免费提供给研究人员，进一步促进了科学研究。最后，关于控制突触发育和可塑性的分子和细胞机制的基础知识为开发未来对社会普遍有益的神经生物学应用提供了坚实的基础。