The role of NCK1 in CSF3R-driven myeloproliferative neoplasms

项目总结 集落刺激因子3受体(CSF3R)是驱动成熟细胞产生的主要受体 中性粒细胞，激活信号通路，控制增殖和分化转录程序。 CSF3R在预后不良的骨髓增生性肿瘤(MPN)中反复突变。这些突变会激活 CSF3R通过JAK/STAT和MAPK通路增强信号，导致生产过剩 中性粒细胞。药物开发工作的重点一直是针对JAK/STAT的激活。然而，最近 研究表明，增强的MAPK信号通路在疾病病理生物学中可能同样重要。 CSF3R激活MAPK通路的确切机制尚不完全清楚。识别 将CSF3R与MAPK信号联系起来的新参与者将提供新的治疗靶点来探索，并允许 更好地了解正常和异常血液学中的CSF3R信号。 使用蛋白质-蛋白质相互作用屏幕，我确定了几个已知的CSF3R相互作用伙伴 调节MAPK通路的激活，包括信号转接子NCK1。我的初步数据显示，NCK1 在MAPK通路的激活中起关键作用，在CSF3RT618I驱动的增殖中是必需的。我 假设NCK1是CSF3R驱动的MAPK通路激活和髓系的重要调节因子 扩散。在目标1中，我将绘制NCK1到CSF3R必需的区域和残基 增强MAPK活性，确立NCK1在骨髓增殖性转录调控中的作用 程序。在目标2中，我将研究NCK1是如何控制髓系分化的，并确定NCK1 在体内CSF3RT618I驱动的骨髓增殖性肿瘤的生物发生中需要表达。这些 实验将揭示NCK1在CSF3R驱动的MAPK通路激活中的作用及其在正常和 异常的造血功能。 这项奖学金将为我的学术生涯的下一阶段做好准备，为我提供新的工作技能 通过活体模型和转录本，加强了我对血液病的理解，并支持 我的职业发展。在NRSA奖学金期间，我将得到朱莉娅·马克森博士和杰弗里博士的指导 泰纳，他们是杰出的顾问，随时准备支持我的成长和项目开发。

PROJECT SUMMARY Colony Stimulating Factor 3 Receptor (CSF3R) is the primary receptor that drives the production of mature neutrophils, activating signaling pathways to control proliferative and differentiation transcriptional programs. CSF3R is recurrently mutated in poor-prognosis myeloproliferative neoplasms (MPNs). These mutations activate CSF3R to enhance signaling through the JAK/STAT and MAPK pathways, resulting in an overproduction of neutrophils. Drug development efforts have been focused on targeting the JAK/STAT activation. However, recent studies have shown that enhanced MAPK pathway signaling may be equally important in disease pathobiology. The precise mechanisms by which CSF3R activates the MAPK pathway are not fully understood. Identifying novel players linking CSF3R to MAPK signaling would offer new therapeutic targets to explore, and allow for a greater understanding of CSF3R signaling in normal and aberrant hematology. Using a protein-protein interaction screen, I identified several CSF3R interacting partners that are known to modulate MAPK pathway activation, including the signaling adapter NCK1. My preliminary data shows that NCK1 plays critical role in activation of the MAPK pathway and is required in CSF3RT618I-driven proliferation. I hypothesize that NCK1 is an essential regulator of CSF3R-driven MAPK pathway activation and myeloid proliferation. In Aim 1, I will map the essential regions and residues of CSF3R that are necessary for NCK1 to potentiate MAPK activation, and establish a role for NCK1 in the control of myeloproliferative transcriptional programs. In Aim 2 I will investigate how NCK1 controls myeloid differentiation, and determine whether NCK1 expression is required for the biogenesis of CSF3RT618I-driven myeloproliferative neoplasms in vivo. These experiments will uncover the role of NCK1 in CSF3R-driven MAPK pathway activation and its role in normal and aberrant hematopoiesis. This fellowship will prepare me for the next stage in my academic career by providing me with new skills working with in vivo models and transcriptomics, strengthening my understanding of hematologic disease, and supporting my professional development. During the NRSA fellowship I will be mentored by Dr. Julia Maxson and Dr. Jeffrey Tyner, who are exceptional advisors and well poised to support my growth and project development.