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: 7530462
• 负责人: Jing-Ruey Joanna Yeh
• 金额: $ 13.18万
• 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/7530462
• 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; Class; Data; Development; Developmental Biology; Disease; Dominant-Negative Mutation; Elderly; Embryo; Erythropoiesis; Fishes; Foundations; Genes; Genetic screening method; Genome; 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; Rate; Research; Research Personnel; Resistance; Role; Supervision; Testing; Therapeutic; Toxic effect; Transgenic Organisms; Whole Organism; Work; Zebrafish; age group; age related; chemical genetics; 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）：急性骨髓性白血病（AML）是一种流行的，致命的疾病，在老年人。急性淋巴细胞白血病（ALL）的发病率在不同年龄组的人群中几乎保持不变，而AML的发病率随着年龄的增加而急剧增加，这表明年龄与AML发病机制之间存在强烈的相关性。该研究旨在（1）确定AML患者中发现的两种常见突变如何导致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的潜在新型治疗方法。实验将利用各种独特的斑马鱼模型，使人类癌基因的诱导表达。斑马鱼已经成为一种强大的脊椎动物模式生物，因为它非常适合遗传和化学扰动。已有十几种斑马鱼突变体被证明重现了人类血液病的特征，表明斑马鱼和人类之间的造血系统高度保守。这项研究不仅将为AML的发病机制提供新的见解，还将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发现的斑马鱼AML样表型的新化学抑制剂。这些化合物的进一步表征可能有助于开发更有效和更安全的AML治疗药物。候选人有癌症和分子生物学的背景，现在寻求扩大她的科学专业知识，并围绕癌症，衰老和化学生物学开发一个研究计划。候选人将在Randall Peterson博士的监督下进行研究。彼得森博士以其将化学遗传工具和斑马鱼发育生物学结合起来用于心血管研究的开创性工作而闻名。候选人还组建了一个顾问小组，其中包括癌症，造血和衰老方面的领导者。赞助商和顾问将与候选人密切互动，并在科学和专业发展方面指导她。最终，该计划将促进候选人成为癌症和衰老独立调查员的目标。