Fine-tuning CXCL12-mediated activities using Beta1-strand binding peptides

使用 Beta1 链结合肽微调 CXCL12 介导的活性

基本信息

批准号：
10796003
负责人：
DIDIER DREAU
金额：
$ 46.2万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2026-09-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10796003
关键词：
Affect Atherosclerosis Autoimmune Diseases Binding Biochemical Biological Biological Sciences Biomedical Research Biophysics Blood Platelets Breast Cancer Cell CXCL9 gene CXCR CXCR4 Receptors CXCR4 gene Cell Communication Cell physiology Cells Characteristics Co-Immunoprecipitations Communication Complex Computer software Data Disease Disease Progression Educational process of instructing Environment Epithelial Cells Epithelium Goals Heterodimerization Human IL8 gene In Vitro Individual Inflammation Institution Investigation Knowledge Laboratory Research Length Leukocytes Machine Learning Macrophage Malignant Neoplasms Mediating Modeling Mus North Carolina Optics PPBP gene Pathologic Pathology Peptides Physics Physiological Process Proliferating Public Health RANTES Receptor Signaling Research Research Technics Role Science Signal Transduction Stromal Cell-Derived Factor 1 Students System Testing Time Training Universities Work biophysical techniques cancer cell career cell motility cell type chemokine chemokine receptor effective therapy experience experimental study glycosaminoglycan receptor immunoregulation improved in silico in vivo intermolecular interaction migration monocyte monomer mutation screening new therapeutic target novel peer peptidomimetics prevent programs receptor skills success therapeutic target training opportunity undergraduate student

项目摘要

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.

抽象的 CXCR4/CXCR7-CXCL12 信号传导关键地调节免疫和癌细胞功能。其他人已经确定了趋化因子异二聚体的存在和潜力，尤其是 CXCL4-CXCL12 与 CXCL12-CXCR4 信号传导的抑制相关，这表明存在一种新的调控目标机制。这些新发现的相互作用（包括 CXCL4-CXCL12）的生物学后果此外，CXCL4-CXCL12 趋化因子是否异源尚未研究。二聚化是否可以作为阻止 CXCL12 驱动的细胞功能的治疗靶点尚不清楚。因此，我们将测试 CXCL12 ß1 链结合肽的假设，模仿 CXCL4 与 CXCL12 的界面，严重影响明确的 CXCL12-CXCR4/ 中的信号传导和生物活性具体来说，我们将确定 CXCR7 驱动的信号传导的抑制潜力。 CXCL12-CXCR4/CXCR7 中的肽驱动巨噬细胞和上皮细胞中的信号传导。研究的重叠具体目标将定义结合特征并优化 CXCL12 ß1- 链结合肽（目标 1）；并确定 CXCL12 的功能信号调节潜力将 ß1 链结合肽分别连接至 CXCR4 和 CXCR7（目标 2），我们将评估 CXCL12-。 CXCL12 ß1 链结合肽异二聚体信号传导至 CXCR4 和 CXCR7 相关功能对关键细胞功能的活性，以及促进稳定 CXCL12- 的生物物理条件 CXCL12 ß1 链结合肽相互作用和特异性 CXCL12 ß1 链结合的潜力肽抑制 CXCL12-CXCR4/CXCR7 信号传导并调节 CXCL12 驱动的细胞功能。总之，通过完成与完成相关的实验而收集的数据提出的目标将更好地理解 CXCR4 上的 CXCL12 异二聚体信号传导以及 CXCR7 和 CXCL12 ß1 链结合肽在防止改变 CXCL12 驱动的方面的潜力基于这些结果并针对趋化因子的异嗜性相互作用，我们的长期目标是对趋化因子的功能有一个基本的了解趋化因子信号传导中的异二聚体及其作为预防疾病进展的靶点的潜力。该项目将使本科生接触到一个综合的、跨学科的研究环境扩大生物科学、物理和光学科学系的培训机会北卡罗来纳大学夏洛特分校是一所快速发展的城市机构，致力于加强其该项目已经通过 PI 吸引了许多本科生。和co-I的课堂教学，并将进一步为本科生提供实验室的实践经验研究技术并向他们介绍生物医学研究的职业生涯。各级同伴培训，包括强调职业成功所需的技能，例如团队合作和沟通。