Role of aberrant cytokine signaling in myeloproliferative disorders

 应聘者：我的最终职业目标是成为一名独立的实验室调查员，专注于血液学翻译研究。我的目标是成为一个研究项目的负责人，该项目旨在阐明血液系统恶性肿瘤中炎症的分子机制，并将基础研究成果转化为新的治疗方法。为了实现我的目标，莱文博士和我制定了一个包含四个关键要素的职业发展计划：1)拓展和加强我的实验和数据分析技能。2)加强我的领导和指导技能，3)从莱文博士和我的顾问委员会那里获得关于我研究进展的建议，以磨练我的批判性思维和科学推理能力，以及4)在R00期间从指导阶段过渡到独立的终身教职跟踪职位。我计划通过参加(内部和外部)会议、互动研讨会和教学会议来解决这些关键要素。此外，我的合作者范博士、布拉德纳博士和巴特勒博士致力于通过提供试剂和专业知识来支持这个项目和我的职业发展。在整个赠款期间，我将得到我的导师Levine博士以及我的顾问委员会成员Aifantis、Armstrong和Lowe博士的支持和指导。在奖项的R00阶段，我将继续与血液学和炎症领域的专家建立成功的合作关系。我将重点研究MPD慢性炎症的分子机制，并将这些发现转化为潜在的新疗法。重要的是，在获奖期间建立强大的研究团队将使我能够确保未来为我自己的实验室提供资金。环境建议的研究将在纪念斯隆-凯特琳癌症中心(MSKCC)进行，该中心以其卓越的病人护理、最先进的设施、创新的研究和出色的教育项目而闻名。作为Levine实验室的一员，我们是人类肿瘤学和病理学计划的一部分，该计划将对基于机制的实验室和翻译研究感兴趣的科学家聚集在一起。在Charles Sawyers博士的领导下，Hopp创造了一个高度协作的环境，这将极大地促进我的翻译研究工作。此外，我将得到我的导师罗斯·莱文博士的持续指导和支持，他是一位杰出的内科科学家和MPD领域的领导者。研究BCR-ABL阴性的骨髓增殖性疾病(MPD)、原发性骨髓纤维化(PMF)和PV/ET后的骨髓纤维化(MF)与显著的发病率和降低死亡率、进行性骨髓纤维化和由此导致的骨髓衰竭相关。PMF患者患有进行性贫血、骨髓重塑、脾肿大、全身症状，并进展为急性白血病。MPD患者的特点是由循环细胞因子升高介导的全身炎症，这些细胞因子被认为是导致骨髓纤维化、体质症状、疾病发病机制和白血病进展的重要因素。接受JAK抑制剂治疗的MPD患者的躯体症状有显著改善，这与血浆细胞因子水平显著降低有关。然而，异常细胞因子产生的介质、异常细胞因子信号转导的特定人群以及JAK抑制剂逆转炎症的机制尚未在临床前或临床环境中进行研究。我们最近证明，非突变细胞中JAK-STAT的激活参与了MPD的发病，突变和非突变细胞中的JAK激酶抑制是改善症状和降低疾病严重性所必需的。我们的初步结果表明，在MPD中，STAT3/NFkB调节的转录机制驱动细胞因子信号转导，而JAK1信号在MPD的发生和发展中是必需的。我们建议剖析在MPD中介导异常炎症信号的机制。在Aim1中，我们将绘制克隆来源的造血细胞、基质细胞和非克隆造血细胞中的细胞因子网络。AIM2被设计用来使用活体模型来分析在MPD中支配细胞因子信号的机制。在Aim3中，我们将阐明靶向治疗扰乱细胞因子网络并影响体内MPD的机制。我们的研究将包括大量人群和单细胞水平上细胞因子产生的详细图谱，调节细胞因子产生的途径的遗传研究，剖析表观遗传疗法对细胞因子表达的作用模式的机制研究，以及旨在减少炎症状态和为未来的临床试验提供信息的临床前治疗研究。这些研究将在指导阶段启动，并将持续到奖项的独立阶段，在此期间，我们将继续我们的机制研究，并努力识别在MPD模型和患者样本中特定干扰宿主免疫反应和细胞因子表达的化合物。

 DESCRIPTION (provided by applicant): Candidate My ultimate career goal is to become an independent laboratory investigator, with a specific focus in hematologic translational research. My goal is to become the leader of a research program that elucidates the molecular mechanisms of inflammation in hematologic malignancies and that translates basic research findings into new therapies. To achieve my goal, Dr. Levine and I have developed a career development plan with four key elements: 1) To expand and strengthen my experimental and data analysis skills. 2) To enhance my leadership and mentoring skills, 3) To receive advice on my research progress from Dr. Levine and my advisory committee in order to hone my critical thinking and scientific reasoning skills, and 4) To transition from the mentored phase to an independent, tenure-track position during the R00 period. I plan to address these key elements by attending (internal and external) meetings, interactive workshops and didactic sessions. In addition, my collaborators Drs. Fan, Bradner, and Butler are committed to support this project and my career development by providing reagents and expertise. Throughout the entire grant period, I will receive support and guidance from my mentor Dr. Levine and my advisory committee members Drs. Aifantis, Armstrong, and Lowe. During the R00 phase of the award, I will continue to build successful collaborations with experts in the fields of hematology and inflammation. I will focus on the investigation of molecular mechanisms underlying chronic inflammation in MPD and to translate these finding into potential new therapies. Importantly, establishing a strong research line during the duration of this award will allow me to secure future funding of my own laboratory. Environment The proposed study will be conduced at Memorial Sloan Kettering Cancer Center (MSKCC), acknowledged for its exceptional patient care, state-of-the-art facilities, innovative research and outstanding educational programs. As a member of the Levine laboratory, we are part of the Human Oncology and Pathogenesis Program that brings together scientists with an interest in mechanism-based laboratory and translational research. Under the leadership of Dr. Charles Sawyers, HOPP creates a highly collaborative environment that will greatly facilitate my translational research efforts. In additin, I will receive continued guidance and support from my mentor, Dr. Ross Levine who is an outstanding physician-scientist and leader in the MPD field. Research The BCR-ABL-negative myeloproliferative disorders (MPD), primary myelofibrosis (PMF) and post PV/ET myelofibrosis (MF) are associated with significant morbidity and reduced mortality, progressive bone marrow fibrosis and resultant bone marrow failure. PMF patients suffer progressive anemia, remodeling of the bone marrow, splenomegaly, systemic symptoms, and progression to acute leukemia. MPD patients are characterized by systemic inflammation mediated by elevated circulating cytokines, which are presumed to contribute to bone marrow fibrosis, constitutional symptoms, disease pathogenesis and leukemic progression. MPD patients treated with JAK inhibitors experience a significant improvement in constitutional symptoms, which correlates with a marked reduction in plasma cytokine levels. However, the mediators of aberrant cytokine production, the specific populations responsible for aberrant cytokine signaling, and the mechanisms by which JAK inhibitors reverse inflammation have not been investigated in preclinical or clinical contexts. We recently demonstrated that JAK-STAT activation in non-mutant cells contributes to MPD pathogenesis and that JAK kinase inhibition in both mutant and non-mutant cells is required to improve symptoms and reduce disease severity. Our preliminary results suggest that STAT3/NFkB-regulated transcriptional mechanisms drive cytokine signaling in MPD, and that JAK1 signaling is required for MPD pathogenesis and progression. We propose to dissect the mechanisms that mediate aberrant inflammatory signaling in MPD. In Aim1, we will map out cytokine networks in clonally derived hematopoietic cells, in stromal cells, and in non-clonal hematopoietic cells. Aim2 is designed to analyze the mechanisms that govern cytokine signaling in MPD using in vivo models. In Aim3, we will elucidate the mechanisms via which targeted therapies can perturb cytokine networks and impact MPD in vivo. Our studies will include detailed mapping of cytokine production in bulk populations and on a single cell level, genetic studies of pathways mediating cytokine production, mechanistic studies to dissect the mode of action of epigenetic therapies on cytokine expression, and preclinical therapeutic studies aimed to reduce the inflammatory state and to inform future clinical trials. These studies will be initiated during the mentored phase, and will continue into the independent stage of the award, during which we will continue our mechanistic studies and work to identify compounds that would specifically interfere with the host immune response and cytokine expression in MPD models and patient samples.