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

摘要 炎性趋化因子CCL2及其G蛋白偶联受体引导单核细胞向组织内迁移 CCR2是正常生理和包括神经退行性变在内的许多疾病的病理的关键， 创伤性脑损伤、关节炎、糖尿病肾病和非酒精性脂肪肝。然而，尽管它的 治疗意义，CCR2在单核细胞功能中的作用仍然知之甚少。除了它的油井- 公认的促进细胞运动的能力，CCR2拥有不同的，同样重要的，但在很大程度上 未被重视的功能：它清除和去除细胞外介质中的趋化因子。拾荒者可能 使表达CCR2的细胞在没有趋化因子浓度增加的情况下沿梯度移动 它还可能通过改变CCL2和CCL2的可用性来调节细胞间的协调和串扰。 其他趋化因子作用于不同细胞上的受体。 本申请是R01GM136202的补充，标题为：驱动细胞移动的信号电路和 趋化因子受体CCR2的配体清除“，并授予Pis Handel和Kufareva 2020-24年度。母公司提案的目标是实现一个全面的、基于预测的系统 了解CCR2迁移和清理功能。实验和计算的进展是 在母公司R01第一年的所有三个目标上提出的申请者表明，需要更好的， CCR2转运、相互作用组和磷酸化的计算模拟的系统和定量平台 发信号。这些发现中的许多都是一位才华横溢的西班牙裔本科生的工作成果 学生Alexis Lona目前是Kufareva实验室的兼职志愿者实习生，但正在寻找更广泛的 和有组织的培训/参与。这一补充将使Alexis能够最好地解决不断增长的 家长R01的计算需求，同时增强他的研究能力，并最终 帮助他实现了成为一名医学科学家的长期职业目标。 申请者将追求两个科学目标，都与父母R01的目标2和3有关。在目标S1中，他将 建立基于电子代理的CCR2交易和交互建模以及建模的框架 对照无偏的邻近生物素化数据进行校准。在目标S2中，实习生将制定一种方法，以 从多因子时间分辨模拟CCR2下游的磷信号传播 磷酸蛋白质组学数据。科学目标得到了全面的培训和指导的补充 旨在构建和促进应聘者研究和职业发展的计划。 作为一名西班牙裔学生，Alexis将通过成为研究实验室的一部分来促进科学的多样性，并通过 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 科学是为他人服务的，同时在他的社区行医。此外，通过分享 亚历克西斯在科学和研究方面的经验旨在为其他有类似背景的人提供信息和启发。

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.