Molecular Recognition Principles, Engineering and Function of Neural Wiring Receptors

神经布线受体的分子识别原理、工程和功能

• 批准号: 9083633
• 负责人: Engin Ozkan
• 金额: $ 36.21万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9083633
• 关键词: Address; Adhesions; Affinity; Autistic Disorder; Binding; Biochemical; Biological Assay; Biological Neural Networks; Biology; Biophysics; Brain; Cell Adhesion; Cell Aggregation; Cell Surface Proteins; Cell Surface Receptors; Cell model; Cell-Cell Adhesion; Cells; Code; Collection; Complex; Crystallography; Development; Disease; Drosophila genus; Engineering; Event; Family; Future; Generic Drugs; Genes; Goals; Hand; Human; Immunoglobulins; In Vitro; Label; Lead; Learning; Libraries; Mediating; Modeling; Molds; Molecular; Monitor; Mutation; Names; Nervous system structure; Neurodevelopmental Disorder; Neurons; Neurophysiology - biologic function; Optic Lobe; Pathway interactions; Perception; Physiological; Physiology; Process; Property; Protein Family; Proteins; Role; Schizophrenia; Sensory Receptors; Signal Pathway; Signal Transduction; Signaling Molecule; Specific qualifier value; Specificity; Structure; Surface Plasmon Resonance; Synapses; System; Techniques; Tertiary Protein Structure; Testing; Time; Transforming Growth Factor beta; Translating; Work; base; biophysical techniques; brain cell; cross reactivity; extracellular; in vivo; inhibitor/antagonist; innovation; leucine-rich repeat protein; member; molecular recognition; neural circuit; neuromechanism; novel; public health relevance; receptor; relating to nervous system; screening; synaptogenesis; targeted treatment; tool

 DESCRIPTION (provided by applicant): Neural connectivity, the collection of synapses wiring nervous system cells, is a major property of a nervous system, and a determinant of neural function. In humans, billions of neurons make trillions of synapses, and the proper function of this system depends on proper wiring. Incorrect wiring of neurons can lead to improper perception and various neurodevelopmental diseases. While it is generally accepted that the connectivity is determined by cell surface receptors that uniquely label neurons and mechanistically guide their wiring, we know a relatively few number of these receptors. Given the complexity of nervous systems, we need to discover more neural receptors and learn how they function, so as to be able to understand brain development and the physiology of diseases where neural wiring is central. To address this, we are working to reveal the identity and physiological function of cell surface receptors that uniquely label neurons and guide their wiring. Previously, using a biochemical approach (protein interaction screening), we have identified two protein families, Dprs and DIPs in Drosophila, that are determinants of neural connectivity, and are a unique case of an "interaction code" that likely guides synaptic pairing of neurons in the brain. Members of Dpr and DIP families bind each other not in a simple one-to-one fashion; each Dpr and DIP interacts with many DIPs and Dprs, a phenomenon we call "cross-reactivity", and mediates a unique set of interactions. In addition, we have discovered a secreted protein we have named common DIP (cDIP), which binds 21 out of 30 Dprs and DIPs, and likely has a regulatory function on Dpr/DIP-mediated neural connections. Here, we propose to reveal the molecular principles that establish this code, which includes 57 interactions, and study the biology of Dpr/DIP- guided synapse formation in vitro, in culture and in vivo. Our multi-faceted approach includes (1) a biophysical and structural characterization of the Dpr-DIP interactions, followed by engineering of Dprs and DIPs to create novel molecular affinities to be tested for novel neural connectivity in the Drosophila brain; (2) a cellular study of Dpr-DIP mediated adhesions and the effect of the common DIP on these cell adhesions; and (3) the creation of a cell-based system for studying the signaling of Dprs and DIPs via the TGF-β/BMP signaling pathway.

 描述（由申请人提供）：神经连接是连接神经系统细胞的突触的集合，是神经系统的主要特性，也是神经功能的决定因素。在人类中，数十亿个神经元形成数万亿个突触以及其适当的功能。该系统的正常连接取决于神经元的正确连接，但人们普遍认为连接性是由细胞表面受体决定的，这些受体独特地标记神经元并机械地引导它们。由于神经系统的复杂性，我们对这些受体的了解相对较少，因此我们需要发现更多的神经受体并了解它们的功能，以便能够了解神经线路所在的大脑发育和疾病的生理学。为了解决这个问题，我们正在努力揭示细胞表面受体的身份和生理功能，这些受体独特地标记神经元并指导其连接，此前，我们使用生化方法（蛋白质相互作用筛选）鉴定了两个蛋白质家族：Dprs 和 Dprs。果蝇中的 DIP，它们是神经连接的决定因素，并且是“交互代码”的独特情况，可能指导突触配对 Dpr 和 DIP 家族的神经元并非以简单的一对一方式相互结合；每个 Dpr 和 DIP 与许多 DIP 和 Dpr 相互作用，这种现象我们称为“交叉反应性”，并介导一种独特的作用。此外，我们还发现了一种分泌蛋白，我们将其命名为常见 DIP (cDIP)，它与 ​​30 个 Dpr 和 DIP 中的 21 个结合，并且可能具有调节功能。在这里，我们建议揭示建立该密码的分子原理，其中包括 57 种相互作用，并在体外、培养物和体内研究 Dpr/DIP 引导的突触形成的生物学。 -多方面的方法包括（1）Dpr-DIP相互作用的生物物理和结构表征，然后对Dprs和DIP进行工程设计，以创建新的分子亲和力，以测试果蝇大脑中新的神经连接； (2) Dpr-DIP 介导的粘附以及常见 DIP 对这些细胞粘附的影响的细胞研究；以及 (3) 创建基于细胞的系统，用于研究 Dprs 和 DIP 通过 TGF-β/ 的信号传导； BMP 信号通路。