Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2

趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路

• 批准号: 10488001
• 负责人: Tracy M Handel
• 金额: $ 2.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488001
• 关键词: Address; Arthritis; Award; Biotinylation; CCL2 gene; Calibration; Cells; Communities; Complement; Computer Models; Data; Diabetic Nephropathy; Disease; G-Protein-Coupled Receptors; Goals; Hispanic; Inflammatory; Internships; Ligands; Mediating; Medical; Medicine; Mentors; Methodology; Modeling; Nerve Degeneration; Parents; Pathology; Physiology; Research; Role; Science; Scientist; Services; Signal Transduction; Structure; Students; System; Talents; Therapeutic; Time; Tissues; Training; Training Support; Training and Education; Traumatic Brain Injury; Work; base; career; career development; cell motility; chemokine; chemokine receptor; computational platform; desensitization; design; experience; extracellular; in silico; migration; monocyte; monocyte chemoattractant protein 1 receptor; non-alcoholic fatty liver disease; parent grant; phosphoproteomics; receptor; research and development; therapeutic target; trafficking; undergraduate student; volunteer

Abstract Monocyte migration into tissues, guided by inflammatory chemokine CCL2 and its G protein-coupled receptor CCR2, is key to normal physiology and to the pathology of numerous diseases including neurodegeneration, traumatic brain injury, arthritis, diabetic nephropathy, and non-alcoholic fatty liver disease. However, despite its therapeutic significance, the role of CCR2 in monocyte function is still poorly understood. In addition to its well- recognized ability to promote cell movement, CCR2 possesses a different, equally important but largely unappreciated function: it scavenges and removes chemokines from the extracellular medium. Scavenging may enable CCR2-expressing cells to move along gradients of increasing chemokine concentration without desensitizing; it may also mediate intercellular coordination and crosstalk by altering the availability of CCL2 and other chemokines to their receptors on different cells. The present application is a supplement to R01 GM136202 titled “Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2,” and awarded to PIs Handel and Kufareva for the period of 2020-24. The objective of the parent proposal is to achieve a comprehensive and predictive systems-based understanding of CCR2 migration and scavenging functions. The experimental and computational advances that the applicants made on all three Aims of the parent R01 during its first year revealed the need for better, systematic and quantitative platforms for computational modeling of CCR2 trafficking, interactome, and phospho- signaling. Many of these findings materialized as a result of the work of a talented Hispanic undergraduate student, Alexis Lona, who is currently a part-time volunteer intern in the Kufareva lab but seeks a more extensive and structured training/engagement. This supplement will enable Alexis to best address the growing computational needs of the parent R01 while at the same time enhancing his research capability and ultimately helping him achieve his long-term career goal of becoming a medical scientist. The applicant will pursue two scientific Aims, both related to Aims 2 and 3 of the parent R01. In Aim S1, he will build a framework for in silico agent-based modeling of CCR2 trafficking and interactions and for model calibration against unbiased proximity biotinylation data. In Aim S2, the trainee will develop a methodology for the modeling of phospho-signal propagation downstream of CCR2 from multifactorial time-resolved phosphoproteomics data. The scientific Aims are complemented by a comprehensive training and mentoring plan designed to structure and facilitate the research and career development of the candidate. As a Hispanic student, Alexis will promote diversity in science by being part of a research lab, and medicine by becoming a medical scientist and professional. With proper education and training, Alexis will be able to further science as a service to others while simultaneously practicing medicine in his community. Moreover, by sharing his experiences in science and research Alexis intends to inform and inspire others from similar backgrounds.

抽象的 单核细胞迁移到组织中，在炎性趋化因子CCL2及其G蛋白偶联接收器的指导下 CCR2是正常生理的关键，也是许多疾病的病理学，包括神经退行性的疾病， 创伤性脑损伤，关节炎，糖尿病性肾病和非酒精性脂肪肝病。但是，它 治疗意义，CCR2在单核细胞功能中的作用仍然鲜为人知。除了它的良好 公认的促进细胞运动的能力，CCR2具有不同的，同样重要但很大程度上 未欣赏的功能：它清除并去除细胞外培养基中的趋化因子。清除五月 使表达CCR2的细胞能够沿着趋化因子浓度升高而无需移动 脱敏它还可以通过改变CCL2和 在不同细胞上对其接收器的其他趋化因子。 本应用是R01 GM136202的补充 趋化因子接收器CCR2的配体清除，并授予PIS Handel和Kufareva 2020-24。父母建议的目的是实现一个全面的，基于系统的全面 了解CCR2迁移和清除功能。实验和计算进步 申请人在父母的第一年以父母R01的所有三个目标提出的申请人表明，需要更好的， 用于CCR2运输，Interactome和磷酸化计算建模的系统和定量平台 信号。由于有才华的西班牙裔本科生的工作，其中许多发现构成了这些发现 学生Alexis Lona，目前是Kufareva实验室的兼职志愿者实习生，但寻求更广泛的 和结构化培训/参与。这种补充剂将使亚历克西斯能够最好地解决增长 父母R01的计算需求同时增强了他的研究能力并最终 帮助他实现成为医学科学家的长期职业目标。 申请人将追求两个科学目标，均与父母R01的目标2和3有关。在AIM S1中，他会 为基于硅代理的CCR2运输和互动建立一个框架 针对无偏接近生物素化数据的校准。在AIM S2中，学员将开发一种方法 从多因素时间分辨的CCR2下游磷酸化信号传播的建模 磷蛋白质组学数据。科学目标是通过全面的培训和心理完成的 计划旨在构建和促进候选人的研究和职业发展。 作为西班牙裔学生，亚历克西斯（Alexis）将成为研究实验室的一部分，并通过 成为医学科学家和专业人士。通过适当的教育和培训，亚历克西斯将能够进一步 科学作为对他人的服务，同时在他的社区中执业。而且，通过分享 他在科学和研究方面的经验亚历克西斯（Alexis）打算从类似背景的情况下告知和启发他人。