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: 8318034
• 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/8318034
• 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.

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.该建议的具体目的是（1）对JAK2V617F突变体HSC进行详细的功能表征； （2）研究TET2损失对JAK2V617F介导的MPN的影响，（3）确定JAK2V617F突变体HSC中的分子依赖性和合作途径。 MPN是造血的克隆疾病，其特征是成熟血细胞的积累和相关并发症的发展。 JAK2V617F功能获得突变是MPN中最常见的分子异常，重要的是它在HSC室中产生。因此，它仍然是MPN中一个有吸引力的治疗靶标，尽管迄今为止，使用小分子JAK2激酶抑制剂直接靶向它的努力仍无法选择性地，始终如一地减少MPN患者的JAK2V617F突变体克隆。该提案的主要目的是对正常和JAK2V617F突变体HSC之间的差异获得生物学理解，并在此过程中确定MPN干细胞的治疗性敏感性，以便将它们有效地靶向确定消除疾病维持MPN MPN克隆。 Mullally博士非常有资格进行该提案中概述的研究，最近在癌细胞中描述了JAK2V617F突变对鼠敲蛋白模型中对造血干细胞和祖细胞的差异作用，这将是该提案中概述的实验中使用的主要生物试剂。在表征JAK2V617F敲蛋白鼠标模型的过程中，Mullally博士在成功完成该提案目标所需的所有技术和方法技能方面都获得了专业知识。在这个K08奖项期间，候选人的主要职业发展目标是获得成为独立医师科学家所需的其他技能。这将通过候选人执行拟议的研究策略来实现，除了她参与了职业发展计划中概述的一系列正式会议和教学教育活动。此外，候选人还组建了一支高度才华横溢的导师，顾问和合作者团队，以使其过渡到独立科学研究员。她的主要导师本杰明·埃伯特（Benjamin Ebert）博士在HSC生物学，红细胞生成和RNA干扰方面的背景方面有能力为该奖项提供专家指导。尽管埃伯特（Ebert）博士在哈佛大学（Harvard）相对较少的教师职位，但已经取得了杰出的学术成就，并因对他的受训者的出色奉献而闻名。此外，候选人将由斯图尔特·奥金（Stuart Orkin）博士共同授予，他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，并且在造血鼠模型中拥有数十年的经验。她的导师将至少每月与候选人会面，以监督和协助她过渡到独立。候选人也很幸运能够继续从加里·吉兰德（Gary Gilliland）博士的指导和专业知识中受益，加里·吉兰德（Gary Gilliland）博士在指导医师 - 科学家以实现独立的指导和专业知识，尽管最近转向行业仍然非常致力于候选人的职业发展。将由候选人咨询委员会任职的斯科特·阿姆斯特朗（Scott Armstrong）博士将提供其他少女专业知识，并被公认为是白血病干细胞生物学领域的领导者。博士。两家部门负责人的南希·伯林纳（Nancy Berliner）和戴维·威廉姆斯（David Williams）都将构成候选人咨询委员会的其余成员，该委员会的其余成员将每六个月至少开会一次，以确保一项成功的科学研究计划。最后，候选人招募了罗斯·莱文（Ross Levine）博士，他是最初描述MPN中JAK2V617F突变的科学研究人员之一，作为其项目的合作者。