Role of aberrant cytokine signaling in myeloproliferative disorders

异常细胞因子信号传导在骨髓增殖性疾病中的作用

• 批准号: 9034064
• 负责人: Maria Kleppe
• 金额: $ 13.77万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034064
• 关键词: Acute leukemia; Address; Advisory Committees; Anemia; Attenuated; Award; Basic Science; Bone Marrow; Cells; Chronic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Committee Members; Constitutional Symptom; Critical Thinking; Cytokine Network Pathway; Cytokine Signaling; Data Analyses; Development Plans; Disease; Disease Progression; Disease model; Educational workshop; Elements; Enhancers; Environment; Epigenetic Process; Funding; Future; Genetic; Genetic study; Goals; Grant; Hematologic Neoplasms; Hematology; Hematopoietic; Heterogeneity; Human; Immune response; Inflammation; Inflammatory; Investigation; JAK1 gene; JAK2 gene; Janus kinase; Laboratories; Laboratory Research; Leadership; Malignant - descriptor; Maps; Mediating; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Mentors; Modeling; Molecular; Morbidity - disease rate; Mutation; Myelofibrosis; Myeloproliferation; Myeloproliferative disease; Non-Malignant; Outcome; Output; Pancytopenia; Pathogenesis; Pathologic; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phase; Physicians; Plasma; Population; Positioning Attribute; Primary Myelofibrosis; Production; Quality of life; Reagent; Recurrence; Research; Research Personnel; Retrospective Studies; Role; STAT3 gene; Sampling; Scientist; Secure; Severity of illness; Signal Transduction; Signaling Molecule; Source; Spleen; Splenomegaly; Staging; Stromal Cells; Symptoms; Therapeutic Studies; Translating; Translational Research; Work; base; bcr-abl Fusion Proteins; cancer cell; career; career development; collaborative environment; cytokine; design; experience; experimental analysis; improved; improved outcome; in vivo; in vivo Model; inhibitor/antagonist; innovation; interest; kinase inhibitor; mRNA Expression; meetings; member; mortality; mouse model; mutant; novel therapeutics; oncology; pre-clinical; programs; response; skills; symptomatic improvement; targeted treatment; tenure track; therapeutic target

 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.

 描述（由申请人提供）：候选人我的最终职业目标是成为一名独立的实验室研究员，特别关注血液学转化研究。我的目标是成为一个研究项目的领导者，阐明血液恶性肿瘤炎症的分子机制，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，Levine博士和我制定了一个职业发展计划，其中包括四个关键要素：1）扩展和加强我的实验和数据分析技能。2)为了提高我的领导能力和指导能力，3）从莱文博士和我的咨询委员会那里获得关于我的研究进展的建议，以磨练我的批判性思维和科学推理能力，以及4）在R 00期间从指导阶段过渡到独立的终身职位。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因素。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该项目和我的职业发展。在整个资助期间，我将得到我的导师Levine博士和我的顾问委员会成员Aifantis博士，Armstrong博士和Lowe博士的支持和指导。在R 00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。我将集中研究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，在这个奖项期间建立一个强大的研究线将使我能够确保我自己的实验室未来的资金。环境拟议的研究将在纪念斯隆-凯特琳癌症中心（MSKCC）进行，该中心以其卓越的患者护理、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实验室的成员，我们是人类肿瘤学和发病机制计划的一部分，该计划汇集了对基于机制的实验室和转化研究感兴趣的科学家。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，我将继续得到我的导师罗斯莱文博士的指导和支持，他是一位杰出的医学科学家和MPD领域的领导者。研究BCR-ABL阴性骨髓增生性疾病（MPD）、原发性骨髓纤维化（PMF）和PV/ET后骨髓纤维化（MF）与显著的发病率和死亡率降低、进行性骨髓纤维化和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、全身症状和进展为急性白血病。MPD患者的特征在于由升高的循环细胞因子介导的全身性炎症，其被认为有助于骨髓纤维化、全身症状、疾病发病机制和白血病进展。用JAK抑制剂治疗的MPD患者经历全身症状的显著改善，这与血浆细胞因子水平的显著降低相关。然而，异常细胞因子产生的介质、负责异常细胞因子信号传导的特定群体以及JAK抑制剂逆转炎症的机制尚未在临床前或临床背景下进行研究。我们最近证明，非突变细胞中的JAK-STAT激活有助于MPD发病机制，并且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程度所必需的。我们的初步结果表明，STAT 3/NF κ B调节的转录机制驱动MPD中的细胞因子信号传导，并且JAK 1信号传导是MPD发病和进展所需的。我们建议解剖的机制，介导异常炎症信号在MPD。在Aim 1中，我们将绘制出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。Aim 2旨在使用体内模型分析MPD中控制细胞因子信号传导的机制。在Aim 3中，我们将阐明靶向治疗可以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映射，介导细胞因子产生的途径的遗传研究，解剖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并为未来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，并将继续进入该奖项的独立阶段，在此期间，我们将继续我们的机制研究，并致力于鉴定在MPD模型和患者样本中特异性干扰宿主免疫应答和细胞因子表达的化合物。