Undergraduate Summer Research in Chemical Biology

化学生物学本科暑期研究

• 批准号: 10810210
• 负责人: Ka Ho Leung
• 金额: $ 1.01万
• 依托单位: CLARKSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810210
• 关键词: Administrative Supplement; Anions; Autophagocytosis; Award; Biology; Calcium; Cell membrane; Cells; Chemicals; Chemistry; Chloride Channels; Chlorides; Clinical Trials; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; FDA approved; Fingerprint; Fluorescence; Health; Homeostasis; Human; Human body; Image; Ions; Kidney Calculi; Measurement; Methods; Minor; Mitochondria; Mutation; Organelles; Osteoporosis; Parents; Pathway interactions; Persons; Pharmaceutical Preparations; Physiological; Play; Potassium; Proteins; Proteinuria; Reporter; Reporting; Research; Respiration; Risk; Role; Sodium; Techniques; Three-dimensional analysis; Variant; Work; experience; human disease; interest; quantitative imaging; response; summer research; targeted therapy trials; targeted treatment; tool; undergraduate student; uptake

SUMMARY/ABSTRACT As one of the most abundant anions in the human body, chloride plays a crucial role in human health. Chloride homeostasis is maintained inside the cell while the chloride level is varied based on the function of organelles. Dysregulation of chloride homeostasis caused by the mutation of chloride channels results in various human diseases such as cystic fibrosis (CFTR, >70,000 people worldwide), proteinuria and kidney stones (ClC-5, 39 million people in US), Osteoporosis (ClC-7, 10 million people in US, 43 million people in the risk group). Although five FDA-approved chloride channel modulators have been reported, they only target plasma membrane chloride channels due to the technical barrier. There is no FDA-approved or clinical trial drug that targets organellar chloride channel. The field of chloride channel-targeted therapy is still under-studied (5 FDA-approved drugs, 2 clinical trial) compared to other channels such as calcium, potassium, and sodium. The lack of understanding of the physiological role of organellar chloride and the well-characterized chloride channel are the biggest roadblocks for the development of chloride channel-targeted therapy. Therefore, suitable research tools with a high resolving ability to examine the organelle chloride in live cells is a highly urgent need, which is essential to elucidate the physiological role of organellar chloride and characterize the chloride channel. However, the current chloride measurement with one-dimensional analysis only shows the average ion level. It cannot observe the chloride level change in a minor subset of organelles triggered by the cellular pathway such as STING and autophagy. Furthermore, the typical fluorescence measurement can only tell the variation of the average chloride level (increase, decrease, and no significant change) in certain conditions. The current methods significantly hinder the identification of deactivated cell pathways or protein based on the chloride level measurement. The proposed research integrate organelle selective dual reporters, single organelle measurement, sub- cellular imaging, and the three-dimensional analysis, to fingerprint the chemotype of organelles along with STING pathway, autophagy, and mitochondrial respiration. Completion of the proposed study will find out the physiological role of organellar chloride which shed light on the chloride channel-targeted therapy. The development of the organelle chemotype fingerprinting technique will also provide tools to characterize chloride channels, evaluate chloride channel modulators and identify the deactivated cell pathways or proteins.

摘要/摘要 作为人体中最丰富的阴离子之一，氯化物在人类健康中起着至关重要的作用。氯化物 稳态保持在细胞内部，而氯化物水平根据细胞器的功能而变化。 由氯化物通道突变引起的氯化物稳态失调导致各种人类 诸如囊性纤维化（CFTR，>全球> 70,000人），蛋白尿和肾结石等疾病（CLC-5，39 在美国，有百万人），骨质疏松症（CLC-7，在美国有1000万人，风险组中有4,300万人）。虽然 据报道了五个FDA批准的氯化物通道调节剂，它们仅靶向质膜氯化物 由于技术障碍，频道。没有FDA批准或临床试验药物针对细胞器 氯化物通道。以氯化物通道为目标的治疗领域仍未研究（5种FDA批准的药物，2个 临床试验）与其他通道（例如钙，钾和钠）相比。 缺乏对细胞器氯化物的生理作用和良好特征的生理作用的了解 氯化物通道是开发以氯化物通道靶向治疗的最大障碍。 因此，适当的研究工具具有很高的分辨能力，可以在现场检查细胞器氯化物 细胞是一个高度迫切的需求，这对于阐明细胞器氯化物的生理作用至关重要 并表征氯化物通道。但是，当前的氯化物测量 分析仅显示平均离子水平。它无法观察到一个小子集中的氯化物水平变化 细胞器由细胞途径（例如刺和自噬）触发。此外，典型 荧光测量只能说出平均氯化物水平的变化（增加，降低，无 在某些条件下发生重大变化）。当前的方法显着阻碍了停用的识别 基于氯化物水平测量的细胞途径或蛋白质。 拟议的研究将Organelle选择性双重记者，单细胞器测量，子 - 细胞成像和三维分析，以指纹构成细胞器的化学型和刺激性 途径，自噬和线粒体呼吸。拟议研究的完成将发现 细胞器氯化物的生理作用，它在以氯化物通道为靶向的治疗上亮着。这 Organelle化学型指纹技术的开发还将提供特征氯化物的工具 通道，评估氯化物通道调节剂并识别失活的细胞途径或蛋白质。