Olfactory receptor-based sensors for biomedical applications

项目总结/摘要 嗅觉受体（Olfactory receptors，ORs）是嗅觉系统中最大的化学检测细胞表面受体家族之一， 人类ORs在嗅觉组织之外表达，其中55个ORs在嗅觉组织中异位表达（exORs）。 18种不同的组织，它们驱动组织特异性过程，包括精子趋化性和肌肉 再生然而，大多数exOR没有已知的配体;它们是孤儿，这限制了它们的能力。 了解它们在人类健康中的作用，包括1）阐明exOR下游途径， 内源性组织，2）exOR内源性配体的鉴定，以及最终3）exOR的评估 作为潜在的治疗靶点。在MIRA续约期间，目标是利用基于OR的传感器 生成大量高质量实验exOR-配体数据以训练机器学习的技术 模型来预测36个目前孤立的exOR的配体。这样的算法将大大加速exOR 这是一种去冗余化，并且可能被证明是通用的，使得能够对所有302个孤立OR进行去冗余化。很长的- 我们的目标是使用已鉴定的激活exOR的配体来梳理它们在人类健康中的作用，包括 鉴定内源性exOR配体在其中过表达的组织中的表达，并确定其在组织中的表达。 他们所参与的下游过程。这种理解将使评估exOR成为可能， 治疗靶点，并为新的一流疗法打开大门。 嗅觉受体属于称为G蛋白偶联受体（GPCR）的细胞表面蛋白类。 非感觉GPCR参与了无数的生物过程，从细胞迁移到免疫，使它们 重要的治疗目标。GPCR信号组合，约100个GPCR在哺乳动物中表达 细胞通过总共17种G蛋白亚型进行信号传导-导致GPCR信号传导之间的广泛串扰 途径，通常具有重要的治疗意义。在理解这一程度方面存在着知识差距 GPCR信号通路串扰及其对细胞过程和动物行为的影响。解剖GPCR 信号通路串扰将使得能够1）鉴定GPCR信号通路， 治疗所需的结果，维斯维斯导致副作用的途径， 精确和更安全的治疗方法，以及2）对GPCR信号传导的更细致的理解，这对于 下一代治疗细胞的工程设计。在MIRA更新期间，目标是制定一个 组合激活/失活多种（≥ 3种）GPCR信号通路的化学遗传学工具集， 为了充分剖析GPCR信号串扰及其生物医学效应， 影响长期目标是最终实现多达17种不同GPCR信号的组合控制 途径，提供细胞表型，可以解释如何组合GPCR激活可以 用于开发新疗法，基于GPCR的电路架构可以激发 开发下一代感觉和反应治疗细胞。

Project Summary/Abstract Olfactory receptors (ORs) are one of the largest family of chemical detecting cell-surface receptors in humans. ORs are expressed beyond the olfactory tissue, with 55 ORs highly expressed ectopically (exORs) in 18 different tissues, where they drive tissue-specific processes including sperm chemotaxis and muscle regeneration. The majority of exORs, however, have no known ligands; they are orphans, which limits the ability to understand their role in human health, including 1) elucidation of exOR downstream pathways in the endogenous tissue, 2) the identification of exOR endogenous ligands, and ultimately 3) an assessment of exORs as potential therapeutic targets. During the MIRA renewal period, the goal is to leverage the OR-based sensor technology to generate large sets of high-quality experimental exOR-ligand data to train machine learning models to predict ligands for the 36 currently orphaned exORs. Such an algorithm would vastly accelerate exOR deorphanization, and may prove to be general, enabling the deorphanization of all 302 orphan ORs. The long- term goal is to use the identified ligands that activate the exORs to tease out their role in human health, including identifying the endogenous exOR ligands in the tissues in which they are overexpressed, and determining the downstream processes in which they are involved. This understanding will enable an assessment of exORs as therapeutic targets, and open the door to new, first-in-class therapeutics. Olfactory receptors belong to the class of cell surface proteins called G-protein coupled receptors (GPCRs). Non-sensory GPCRs are involved in a myriad of biological process, from cell migration to immunity, making them important therapeutic targets. GPCRs signal combinatorially, with ~100s of GPCRs expressed in mammalian cells signaling via a total of 17 G-protein subtypes—resulting in extensive crosstalk between GPCR signaling pathways, often with important therapeutic implications. A gap in knowledge exists in understanding the extent of GPCR signaling pathway crosstalk and its effect on cellular processes and animal behavior. Dissecting GPCR signaling pathway crosstalk will enable 1) the identification of GPCR signaling pathways leading to therapeutically desired outcomes, vis a vis pathways leading to side effects, towards the development of more precise and safer therapeutics, and 2) a more nuanced understanding of GPCR signaling that will be crucial for the engineering of next-generation therapeutic cells. During the MIRA renewal period the goal is to develop a chemogenetic toolset to combinatorially activate/deactivate multiple (≥ 3) GPCR signaling pathways while leaving the rest of the cell intact in order to fully dissect the effects of GPCR signaling crosstalk and its biomedical implications. The long-term goal is to ultimately enable combinatorial control of up to 17 different GPCR signaling pathways, providing access to cellular phenotypes that may explain how combinatorial GPCR activation can be leveraged for the development of new therapies and the GPCR-based circuit architecture could inspire the development of next-generation sense and response therapeutic cells.