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

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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.