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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在炎症趋化因子 CCL2 及其 G 蛋白偶联受体的引导下，单核细胞迁移到组织中 CCR2 是正常生理学和多种疾病病理学的关键，包括神经退行性疾病、然而，尽管有外伤性脑损伤、关节炎、糖尿病肾病和非酒精性脂肪肝。除了其治疗意义外，CCR2 在单核细胞功能中的作用仍然知之甚少。 CCR2 具有公认的促进细胞运动的能力，但它具有不同的、同样重要但很大程度上未被重视的功能：它清除细胞外介质中的趋化因子。使 CCR2 表达细胞能够沿着趋化因子浓度增加的梯度移动，而无需脱敏；它还可能通过改变 CCL2 的可用性来介导细胞间协调和串扰其他趋化因子作用于不同细胞上的受体。本申请是对 R01 GM136202 的补充，标题为“驱动细胞运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 期间 2020-24 母提案的目标是实现基于综合性和预测性的系统。了解 CCR2 迁移和清除功能的实验和计算进展。申请人在第一年就母版 R01 的所有三个目标提出的要求表明，需要更好的、用于 CCR2 运输、相互作用组和磷酸化计算建模的系统和定量平台其中许多发现都是由一位才华横溢的西班牙裔本科生的工作成果实现的。学生 Alexis Lona，目前是 Kufareva 实验室的兼职志愿者实习生，但寻求更广泛的机会这种补充将使亚历克西斯能够最好地应对不断增长的问题。父 R01 的计算需求，同时增强他的研究能力，并最终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，均与母体 R01 的目标 2 和 3 相关。在目标 S1 中，他将追求两个科学目标。建立基于计算机代理的 CCR2 贩运和相互作用建模框架以及模型在 Aim S2 中，学员将开发一种方法来进行校准。从多因素时间分辨对 CCR2 下游磷酸信号传播进行建模磷酸蛋白质组学数据的科学目标得到了全面的培训和指导的补充。旨在构建和促进候选人的研究和职业发展的计划。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，并通过通过适当的教育和培训，亚历克西斯将能够进一步成为一名医学科学家和专业人士。科学为他人服务，同时在社区行医。亚历克西斯（Alexis）希望通过他在科学和研究方面的经历为具有类似背景的其他人提供信息和启发。