CAREER: Modulating cell signaling and migration by targeted small-molecule binding to a key regulator of protein degradation

控制细胞死亡是清除不健康细胞的关键，但正在发现有助于不健康细胞存活的新蛋白质。史密斯实验室设计了一种小分子，可以与一种与细胞存活有关的关键蛋白质结合，这种蛋白质被称为含缬草蛋白（VCP）。本项目旨在通过小分子调节VCP的功能，为了解不同疾病的病因提供基础知识，并为未来的治疗提供线索。这个项目将被纳入一个夏季桥梁项目，旨在介绍即将入学的新生到鲍伊州立大学进行研究，这是一所历史悠久的黑人大学（HCBU）。在夏季，学生们将在鲍伊州立大学自然科学系的史密斯实验室和其他合作实验室进行实验室轮转。这些研究经验将通过化学合成、生物信息学、生物化学和分子生物学项目证明结构-功能在小分子-蛋白质相互作用中的重要性。除了研究之外，夏季桥梁课程还将向学生介绍大学水平的生物学、化学、生物信息学和物理学。鉴于提出的强有力的研究和HBCUs的培养环境，参加该计划的学生将拥有在STEM领域取得成功的技能和信心。Valosin-containing protein是一种六聚三磷酸腺苷酶，由于其在泛素-蛋白酶体系统中的作用，它是蛋白质降解的关键。VCP调制的许多下游效应已被确定，包括细胞迁移。然而，目前靶向VCP atp酶活性的小分子是无选择性的。变构结合剂已显示出替代atp酶结合剂的前景，但已观察到获得性耐药。史密斯实验室已经通过分子对接确定了与VCP结合的小分子。这些分子有可能成为了解VCP结合如何通过调节p53和NF-KB影响下游过程（如细胞迁移）的工具。最终，本研究将为VCP在细胞恶性肿瘤中的作用提供新的见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Controlled cell death is key to the removal of unheathy cells but new proteins are being discovered that contribute to the survival of unhealthy cells. The Smith Lab has designed small molecules that bind to a key protein involved in cell survival known as valosin-containing protein (VCP). This project seeks to modulate the function of VCP with small molecules to provide a fundamental understanding of the etiology of different diseases and provide clues to their future treatment. This project will be incorporated into a summer bridge program aimed at introducing incoming freshmen to research at Bowie State University, a Historically Black College & University (HCBU). During the summer students will participate in lab rotations in the Smith and other collaborating labs in the Department of Natural Sciences at Bowie State. These research experiences will demonstrate the importance of structure-function in small molecule-protein interactions through chemical synthesis, bioinformatics, biochemistry, and molecular biology projects. In addition to research, the summer bridge program will introduce students to college-level biology, chemistry, bioinformatics, and physics. Given the robust research proposed and the nurturing environment of HBCUs, students participating in this program will have the skills and confidence to succeed in STEM. Valosin-containing protein is a hexameric ATPase which is key to protein degradation due to its role in the ubiquitin-proteasome system. Many downstream effects of VCP modulation have been identified including cell migration. However current small molecules that target the ATPase activity of VCP are unselective. Allosteric binders have shown promise as alternatives to ATPase binders, however acquired resistance has been observed. The Smith Lab has identified small molecules which bind to VCP through molecular docking. These molecules have the potential to be tools to understand how VCP binding effects downstream processes such as cell migration through regulation of p53 and NF-KB. Ultimately this study will give new insight into the role of VCP in cellular malignancy.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.