Fine-tuning CXCL12-mediated activities using BETA1-strand binding peptides

This Project Grant award from the National Institute of General Medical Sciences (NIGMS) Biomedical Research and Research Training program (CFDA 93.859) aims to define the binding characteristics and functional signaling potential of CXCL12 SS1-strand binding peptides in modulating CXCR4 and CXCR7 receptor activities. The $461,992 award to the University of North Carolina at Charlotte will support research to better understand how CXCL12 chemokine heterodimers regulate immune and cancer cell functions. Specifically, the research will assess the ability of the CXCL12 SS1-strand binding peptides to inhibit CXCL12-driven signaling through the CXCR4 and CXCR7 receptors. The award also seeks to provide undergraduate research training opportunities in this interdisciplinary area of biomedical science.

Abstract

The CXCR4/CXCR7-CXCL12 signaling critically modulate immune and cancer cell functions. Our work and others have established the presence and the potential of chemokine heterodimers especially CXCL4-CXCL12 associated with an inhibition of CXCL12-CXCR4 signaling suggesting a new regulatory targetable mechanism. The biological consequences of these newly discovered interactions including of CXCL4-CXCL12 heterodimers with CXCR7 have not been studied yet. Further, whether CXCL4-CXCL12 chemokine hetero- dimerization may serve as a therapeutic target to prevent CXCL12-driven cell function is unknown. Therefore, we will test the hypothesis that CXCL12 SS1-strand binding peptides, mimicking the CXCL4 interface with CXCL12, critically affect signaling and biological activities in well-delineated CXCL12-CXCR4/ CXCR7 driven signaling. Specifically, we will determine the inhibiting potential of CXCL12 SS1-strand binding peptides in the CXCL12-CXCR4/CXCR7 driven signaling in macrophages and epithelial cells. The non- overlapping specific aims of the study will define binding characteristics and optimize the CXCL12 SS1- strand binding peptides (aim 1); and determine the functional signaling modulating potential of CXCL12 SS1-strand binding peptides onto CXCR4 and CXCR7 (aim 2), respectively. We will assess the CXCL12- CXCL12 SS1-strand binding peptide heterodimer signaling onto CXCR4 and CXCR7 associated functional activities on key cell functions, along with the optimal biophysical conditions promoting stable CXCL12- CXCL12 SS1-strand binding peptide interactions and the potential of specific CXCL12 SS1-strand binding peptides to inhibit CXCL12-CXCR4/CXCR7 signaling and modulate CXCL12-driven cell functions. Together, the data gathered through the completion of the experiments associated with the completion of the proposed aims will yield a better understanding of the CXCL12 heterodimer signaling onto CXCR4 and CXCR7 and the potential of CXCL12 SS1-strand binding peptides in preventing altering CXCL12-driven signaling and functions. Building on these results and targeting heterophilic interactions of chemokines, our long-term goal is to develop a fundamental understanding of the functions of chemokine heterodimers in chemokine signaling and their potential as target to prevent disease progression. This area project will expose undergraduate students to an integrative and cross-disciplinary research environment by extending training opportunities in the departments of biological sciences and physics and optical sciences at the university of north carolina charlotte, a rapidly-growing urban institution that seeks to strengthen its biomedical research program. This project has already attracted many undergraduate students through the PI's and CO-i's classroom teaching and will further provide undergraduates a hands-on experience with laboratory research techniques and introduce them to a career in biomedical research. Students will participate in peer-to- peer training at all levels, including an emphasis on skills needed for professional success such as teamwork and communication.