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: 8164804
• 负责人: Ann Mullally
• 金额: $ 13.66万
• 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/8164804
• 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; 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. PUBLIC HEALTH RELEVANCE: Myeloproliferative neoplasms (MPN) are diseases of the blood and bone marrow, with a prevalence of approximately 80-100,000 cases in the United States, and significant associated problems due to clotting events, bleeding predisposition and risk of transformation of MPN to aggressive leukemias. MPN arises due to the acquisition of genetic abnormalities in the earliest blood-forming cells, the so-called hematopoietic stem cells (HSCs), the most common of which is the JAK2V617F mutation. This proposal seeks to gain biological understanding of the differences between normal and JAK2V617F mutated HSCs, with a view to exploiting these differences therapeutically, and in doing so advance the development of less toxic and more effective treatments for MPN, that specifically target the root cause of the disease, the MPN stem cells.

描述（由申请人提供）：候选人Ann Mullally博士提出了一个为期5年的职业发展计划，旨在研究骨髓增生性肿瘤（MPN）造血干细胞（HSC）的功能和分子特性，使用体内小鼠模型，同时建立作为血液学领域独立医生科学家的学术生涯。本提案的具体目的是（1）对Jak 2 V617 F突变型HSC进行详细的功能表征;（2）研究Tet 2缺失对Jak 2 V617 F介导的MPN的影响;（3）确定Jak 2 V617 F突变型HSC中的分子依赖性和协同作用途径。MPN是造血的克隆性疾病，其特征在于成熟血细胞的积累和与其相关的并发症的发展。JAK 2 V617 F功能获得性突变是MPN中最常见的分子异常，重要的是它出现在HSC区室中。因此，它仍然是MPN中有吸引力的治疗靶标，尽管使用小分子JAK 2激酶抑制剂直接靶向它的努力迄今未能选择性地和一致地减少MPN患者中的JAK 2 V617 F突变体克隆。该提案的主要目标是获得对正常和Jak 2 V617 F突变型HSC之间差异的生物学理解，并在此过程中鉴定MPN干细胞的治疗能力，以便它们可以有效地靶向明确消除维持疾病的MPN克隆。Mullally博士完全有资格进行本提案中概述的研究，最近在Cancer Cell中描述了Jak 2 V617 F突变对小鼠敲入模型中造血干细胞和祖细胞的差异效应，这将是本提案中概述的实验中使用的主要生物试剂。在表征Jak 2 V617 F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。候选人的主要职业发展目标，在此K 08奖期间将获得所需的额外技能，成为一个独立的物理学家，科学家。这将通过候选人执行拟议的研究战略以及参与职业发展计划中概述的一系列正式会议和教学教育活动来实现。此外，候选人还组建了一支由导师、顾问和合作者组成的才华横溢的团队，以指导她向独立科学研究者的过渡。她的主要导师Benjamin Ebert博士在HSC生物学、红细胞生成和RNA干扰方面的背景使他能够为该奖项提供专家指导。尽管他在哈佛的职位相对较低，但埃伯特博士已经取得了非凡的学术成就，并以其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，他曾指导过血液学领域70多位非常成功的学术医生和科学家，并在造血小鼠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，监督和协助她向独立过渡。候选人也很幸运，继续受益于加里Gilliland博士的指导和专业知识，他在指导医生科学家独立方面有着出色的记录，尽管最近搬到了工业界，但仍然非常致力于候选人的职业发展。斯科特·阿姆斯特朗博士将提供额外的鼠类专业知识，他将在候选人的咨询委员会任职，并被公认为白血病干细胞生物学领域的领导者。南希·柏林纳博士和大卫威廉姆斯博士都是有着长期指导记录的部门负责人，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举行一次会议，以确保科学研究项目的成功。最后，这位候选人招募了Ross Levine博士，他是描述MPN中JAK 2 V617 F突变的最初科学研究者之一，作为她项目的合作者。 公共卫生相关性：骨髓增生性肿瘤（MPN）是血液和骨髓的疾病，在美国大约有80- 100，000例患病率，并且由于凝血事件、出血倾向和MPN转化为侵袭性白血病的风险而引起显著的相关问题。MPN的产生是由于最早的造血细胞（所谓的造血干细胞（HSC））中遗传异常的获得，其中最常见的是JAK 2 V617 F突变。该提案旨在获得对正常和JAK 2 V617 F突变的HSC之间差异的生物学理解，以期在治疗上利用这些差异，并在此过程中推进毒性更小且更有效的MPN治疗方法的开发，该治疗方法专门针对疾病的根本原因MPN干细胞。