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

摘要 炎症趋化因子CCL 2及其G蛋白偶联受体介导的单核细胞向组织迁移 CCR 2是正常生理学和许多疾病病理学的关键，包括神经变性， 创伤性脑损伤、关节炎、糖尿病肾病和非酒精性脂肪肝。然而，尽管其 尽管CCR 2在单核细胞功能中的作用具有显著的治疗意义，但对CCR 2在单核细胞功能中的作用仍然知之甚少。除此之外，它的好-- CCR 2具有促进细胞运动的公认能力，具有不同的，同样重要的，但在很大程度上 不受重视的功能：它清除和去除细胞外介质中的趋化因子。清除可以 使表达CCR 2的细胞能够沿着趋化因子浓度增加的梯度移动， 脱敏;它也可以通过改变CCL 2的可用性来介导细胞间的协调和串扰， 其他趋化因子与它们在不同细胞上的受体结合。 本申请是标题为“驱动细胞运动和细胞周期的信号传导电路”的R 01 GM 136202的补充申请。 趋化因子受体CCR 2清除配体”，并授予PI Handel和Kufareva， 2020-24.母提案的目标是实现一个全面的和预测性的基于系统的 了解CCR 2的迁移和清除功能。实验和计算的进步， 在其第一年期间对父R 01的所有三个目标提出的申请揭示了需要更好， CCR 2运输、相互作用组和磷酸化的计算建模的系统和定量平台。 信号这些发现中的许多都是一位才华横溢的西班牙裔大学生的工作成果 学生亚历克西斯·洛纳（Alexis Lona）目前是Kufareva实验室的兼职志愿者实习生，但他正在寻求更广泛的 有组织的培训/参与。这一补充将使亚历克西斯能够最好地解决日益增长的 R 01的计算需求，同时提高他的研究能力， 帮助他实现成为一名医学科学家的长期职业目标。 申请人将追求两个科学目标，均与母公司R 01的目标2和目标3相关。在Aim S1中，他将 建立一个框架，用于CCR 2贩运和相互作用的基于计算机代理的建模，并用于模型 针对无偏邻近生物素化数据进行校准。在目标S2中，受训者将制定一种方法， 从多因子时间分辨的CCR 2的磷酸信号传播下游的建模 磷酸化蛋白质组学数据。科学的目标是由一个全面的培训和指导补充 计划旨在组织和促进候选人的研究和职业发展。 作为一名西班牙裔学生，亚历克西斯将通过成为研究实验室的一部分来促进科学的多样性， 成为一名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 科学作为一种服务他人，同时在他的社区行医。此外，通过分享 他在科学和研究方面的经验，亚历克西斯打算告知和激励来自类似背景的其他人。

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.