Age factors, mutations, and chemical suppressors of acute myelogenous leukemia

急性髓性白血病的年龄因素、突变和化学抑制剂

• 批准号: 7659629
• 负责人: Jing-Ruey Joanna Yeh
• 金额: $ 13.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659629
• 关键词: AML1-ETO fusion protein; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Affect; Age; Age Factors; Aging; Animal Model; Biology; Cardiovascular system; Cell Differentiation process; Cells; Chemicals; Data; Development; Developmental Biology; Disease; Dominant-Negative Mutation; Elderly; Embryo; Erythropoiesis; Fishes; Foundations; Genes; Genetic screening method; Goals; Growth; Heat-Shock Response; Hematological Disease; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; Human Characteristics; In Vitro; Incidence; Leukemic Cell; Malignant Neoplasms; Microarray Analysis; Modeling; Molecular Biology; Mutation; Myeloid Cells; Myeloid Leukemia; Myelopoiesis; Myeloproliferative disease; Oncogenes; Pathogenesis; Patients; Phenotype; Research; Research Personnel; Resistance; Role; Supervision; Testing; Therapeutic; Toxic effect; Transgenic Organisms; Whole Organism; Work; Zebrafish; age group; age related; chemical genetics; genome-wide; in vivo; insight; malignant phenotype; mutant; novel; novel therapeutics; older patient; prognostic; programs; promoter; research study; response; small molecule; t(8; 21)(q22; q22); tool

DESCRIPTION (provided by applicant): Acute myelogenous leukemia (AML) is a prevalent, deadly disease in older adults. Unlike the incidence rate of acute lymphoblastic leukemia (ALL) which stays pretty much the same among people of varying age groups, the incidence rate of AML shows a dramatic increase with increased age, suggesting a strong association between age and AML pathogenesis. The proposed research aims to (1) determine how two of the common mutations found in AML patients contribute to AML pathogenesis; (2) identify age-dependent factors that contribute to AML pathogenesis; and (3) validate potential, novel therapeutics against AML. The experiments will utilize various unique zebrafish models enabling inducible expression of the human oncogenes. The zebrafish has emerged as a powerful vertebrate model organism because it is highly amenable to both genetic and chemical perturbation. More than a dozen zebrafish mutants have been shown to recapitulate the characteristics of human hematological diseases, indicating that the hematopoietic system is highly conserved between zebrafish and humans. The proposed research will not only provide new insights into AML pathogenesis, but also lay a foundation for the use of zebrafish in studying the aging of the hematopoietic system. In addition, the proposed experiments will utilize novel chemical suppressors of the AML-like phenotype in zebrafish that we recently identified. Further characterization of these compounds may prove useful in the development of more effective and safer therapeutics against AML. The candidate has a background in cancer and molecular biology and now seeks to expand her scientific expertise and develop a research program centering around cancer, aging, and chemical biology. The candidate will conduct the research under the supervision of Dr. Randall Peterson. Dr. Peterson is known for his pioneering work on combining chemical genetic tools and zebrafish developmental biology for cardiovascular research. The candidate has also assembled a panel of advisors that include leaders in cancer, hemaotopoiesis, and aging. The sponsor and the advisors will closely interact with the candidate and guide her in both scientific and professional development. Ultimately, this program will facilitate the candidate's goals of becoming an independent investigator in cancer and aging.

描述（由申请人提供）：急性髓性白血病（AML）是老年人中一种流行的致命疾病。与不同年龄组人群中急性淋巴细胞白血病（ALL）的发病率几乎保持不变不同，AML的发病率随着年龄的增加而急剧增加，这表明年龄与AML发病机制之间存在很强的相关性。拟议的研究旨在 (1) 确定 AML 患者中发现的两种常见突变如何促进 AML 发病机制； (2) 确定导致 AML 发病机制的年龄依赖性因素； (3) 验证针对 AML 的潜在新型疗法。这些实验将利用各种独特的斑马鱼模型来诱导表达人类癌基因。斑马鱼已成为一种强大的脊椎动物模式生物，因为它非常容易受到遗传和化学扰动的影响。十多个斑马鱼突变体已被证明能够重现人类血液疾病的特征，这表明斑马鱼和人类之间的造血系统高度保守。该研究不仅将为AML发病机制提供新的见解，而且为利用斑马鱼研究造血系统的衰老奠定基础。此外，拟议的实验将利用我们最近在斑马鱼中发现的 AML 样表型的新型化学抑制剂。这些化合物的进一步表征可能有助于开发更有效、更安全的 AML 疗法。该候选人拥有癌症和分子生物学背景，现在寻求扩大她的科学专业知识，并开发一个围绕癌症、衰老和化学生物学的研究项目。候选人将在兰德尔·彼得森博士的监督下进行研究。彼得森博士以其将化学遗传工具与斑马鱼发育生物学相结合进行心血管研究的开创性工作而闻名。该候选人还组建了一个顾问小组，其中包括癌症、造血和衰老领域的领导者。赞助商和顾问将与候选人密切互动，并指导她的科学和专业发展。最终，该计划将促进候选人成为癌症和衰老领域的独立研究者的目标。