Functional and Molecular Dissection of Myeloproliferative Neoplasm Stem Cells

骨髓增生性肿瘤干细胞的功能和分子解剖

• 批准号: 8514708
• 负责人: Ann Mullally
• 金额: $ 13.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-10 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514708
• 关键词: Advanced Development; Advisory Committees; Award; Biological; Blood; Blood Cells; Bone Marrow; Cells; Chronic Myeloid Leukemia; Clinical Trials; Coagulation Process; Commit; Dedications; Dependency; Development; Development Plans; Disease; Dissection; Educational Activities; Ensure; Erythropoiesis; Erythropoietin; Event; Faculty; Gene Targeting; Genes; Genetic Models; Goals; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Human; Imatinib; Industry; JAK2 gene; Mediating; Mentors; Mentorship; Modeling; Molecular; Molecular Abnormality; Mus; Mutate; Mutation; Myeloproliferative disease; Pathway interactions; Patients; Phase; Phenotype; Physicians; Plant Roots; Polycythemia Vera; Population; Positioning Attribute; Predisposition; Prevalence; Property; Qualifying; RNA Interference; Reagent; Recruitment Activity; Research; Research Personnel; Risk; Role; Scientist; Series; Signal Pathway; Stem cells; Testing; Therapeutic; Transcript; United States; bcr-abl Fusion Proteins; cancer cell; career; career development; design; disease phenotype; effective therapy; experience; gain of function mutation; in vivo; inhibitor/antagonist; kinase inhibitor; leukemia; leukemic stem cell; loss of function mutation; meetings; member; mouse model; mutant; programs; promoter; research study; self-renewal; skills; small hairpin RNA; small molecule; stem; stem cell biology; success; therapeutic target

DESCRIPTION (provided by applicant): The candidate, Dr. Ann Mullally, presents a 5-year career development plan that seeks to investigate the functional and molecular properties of myeloproliferative neoplasm (MPN) hematopoietic stem cells (HSCs), using in vivo murine models, while establishing an academic career as an independent physician-scientist in the field of hematology. The specific aims of this proposal are to (1) perform detailed functional characterization of Jak2V617F mutant HSCs; (2) investigate the effect of Tet2 loss on Jak2V617F mediated MPN and (3) determine molecular dependencies and co-operating pathways in Jak2V617F mutant HSCs. MPN are clonal disorders of hematopoiesis characterized by an accumulation of mature blood cells and development of the associated complications of this. The JAK2V617F gain-of-function mutation is the most common molecular abnormality in MPN, and importantly it arises in the HSC compartment. Therefore, it remains an attractive therapeutic target in MPN, although efforts to target it directly using small molecule JAK2 kinase inhibitors have so far failed to selectively and consistently diminish the JAK2V617F mutant clone in MPN patients. The major goal of this proposal is to gain biological understanding of the differences between normal and Jak2V617F mutant HSCs, and in doing so, to identify the therapeutic susceptibilities of MPN stem cells, so that they can be effectively targeted to definitively eliminate the disease-maintaining MPN clone. Dr. Mullally is well qualified to carry out the research outlined in this proposal, having recently described in Cancer Cell, the differential effects of the Jak2V617F mutation on hematopoietic stem and progenitor cells in a murine knockin model, that will be the main biological reagent utilized in the experiments outlined in this proposal. During the course of characterizing the Jak2V617F knockin mouse model, Dr. Mullally gained expertise in all of the technical and methodological skills required to successfully complete the objectives of this proposal. The candidate's primary career development goal during this K08 award period will be to gain the additional skills required to become an independent physician-scientist. This will be achieved through the candidate's execution of the proposed research strategy in addition to her involvement in a series of formal meetings and didactic educational activities as outlined in the career development plan. Furthermore, the candidate has assembled a highly talented team of mentors, advisors, and collaborators to shepherd her transition to independent scientific investigator. Her primary mentor, Dr. Benjamin Ebert is well positioned to provide expert guidance for this award given his background in HSC biology, erythropoiesis and RNA interference. Despite his relatively junior faculty position at Harvard, Dr. Ebert has already achieved remarkable academic success and has established a reputation for exceptional dedication to his mentees. In addition, the candidate will be co-mentored by Dr. Stuart Orkin, who has mentored more than seventy highly successful academic physicians and scientists in the field of hematology and has decades of experience in murine models of hematopoiesis. Her mentors will meet with the candidate at least monthly to supervise and assist in her transition to independence. The candidate is also fortunate to continue to benefit from the guidance and expertise of Dr. Gary Gilliland, who has an outstanding record of mentoring physician-scientists to independence, and although recently moved to industry remains very committed to the candidate's career development. Additional murine expertise will be provided by Dr. Scott Armstrong, who will serve on the candidate's advisory committee, and is recognized as a leader in the field of leukemia stem cell biology. Drs. Nancy Berliner and David Williams, both division chiefs with a long track record of mentorship, will comprise the remaining members of the candidate's advisory committee, which will meet at minimum, every six months to ensure a successful scientific research program. Finally, the candidate has recruited Dr. Ross Levine, one of the initial scientific investigators to describe the JAK2V617F mutation in MPN, as a collaborator for her project.

描述（由申请人提供）：候选人Ann Mullally博士提出了一个5年的职业发展计划，旨在研究骨髓增殖性肿瘤（MPN）造血干细胞（hsc）的功能和分子特性，使用体内小鼠模型，同时在血液学领域建立一个独立的医生科学家的学术生涯。本提案的具体目的是：(1)对Jak2V617F突变型hsc进行详细的功能表征；(2)研究Tet2缺失对Jak2V617F介导的MPN的影响；(3)确定Jak2V617F突变型hsc的分子依赖性和协同通路。MPN是一种克隆性造血疾病，其特征是成熟血细胞的积累及其相关并发症的发展。JAK2V617F功能获得突变是MPN中最常见的分子异常，重要的是它出现在HSC细胞室中。因此，它仍然是MPN中一个有吸引力的治疗靶点，尽管使用小分子JAK2激酶抑制剂直接靶向它的努力迄今未能选择性地和持续地减少MPN患者中的JAK2V617F突变克隆。本提案的主要目标是获得正常和Jak2V617F突变hsc之间差异的生物学理解，并在此过程中确定MPN干细胞的治疗敏感性，从而可以有效地靶向它们以明确地消除维持疾病的MPN克隆。Mullally博士完全有资格开展本提案中概述的研究，他最近在《癌细胞》（Cancer Cell）中描述了Jak2V617F突变对小鼠敲除蛋白模型中造血干细胞和祖细胞的不同影响，这将是本提案中概述的实验中使用的主要生物试剂。在描述Jak2V617F敲入小鼠模型的过程中，Mullally博士获得了成功完成本提案目标所需的所有技术和方法技能的专业知识。在本次K08奖励期间，候选人的主要职业发展目标将是获得成为独立内科科学家所需的额外技能。除了参与职业发展计划中概述的一系列正式会议和教学性教育活动外，候选人还将通过执行拟议的研究策略来实现这一目标。此外，候选人已经组建了一个由导师、顾问和合作者组成的非常有才华的团队，以指导她向独立科学研究者的过渡。她的主要导师Benjamin Ebert博士凭借其在造血干细胞生物学、红细胞生成和RNA干扰方面的背景，很好地为该奖项提供了专家指导。尽管Ebert博士在哈佛大学的职位相对较低，但他已经取得了显著的学术成就，并以对学生的特殊奉献而闻名。此外，候选人将由Stuart Orkin博士共同指导，Stuart Orkin博士在血液学领域指导了70多名非常成功的学术医生和科学家，并在小鼠造血模型方面拥有数十年的经验。她的导师将至少每月与候选人会面一次，以监督和帮助她过渡到独立。候选人也很幸运能够继续从Gary Gilliland博士的指导和专业知识中受益，Gary Gilliland博士在指导内科科学家独立方面有着出色的记录，尽管最近转到工业界，但他仍然非常致力于候选人的职业发展。斯科特·阿姆斯特朗（Scott Armstrong）博士将担任候选人顾问委员会的成员，他是白血病干细胞生物学领域公认的领导者，将提供额外的小鼠专业知识。Drs。Nancy Berliner和David Williams都是部门主管，有着长期的指导记录，他们将组成候选人咨询委员会的其余成员，该委员会将至少每六个月召开一次会议，以确保科学研究计划的成功。最后，这位候选人招募了罗斯·莱文博士（Ross Levine）作为她项目的合作者，他是最早描述MPN中JAK2V617F突变的科学研究者之一。