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

描述（由申请人提供）：急性髓性白血病（AML）是一种在老年人中普遍存在的致命疾病。不同于急性淋巴细胞白血病（acute lymphoblastic leukemia， ALL）的发病率在不同年龄组的人群中基本保持不变，AML的发病率随着年龄的增长而急剧增加，提示年龄与AML的发病机制有很强的相关性。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AML发病的年龄依赖性因素；(3)验证潜在的抗AML新疗法。实验将利用各种独特的斑马鱼模型来诱导表达人类致癌基因。斑马鱼已经成为一种强大的脊椎动物模式生物，因为它高度适应遗传和化学扰动。十几种斑马鱼突变体已被证明概括了人类血液病的特征，表明造血系统在斑马鱼和人类之间高度保守。本研究不仅将为AML的发病机制提供新的见解，也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样表型的新型化学抑制因子。进一步表征这些化合物可能有助于开发更有效和更安全的AML治疗方法。该候选人具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展研究项目。候选人将在Randall Peterson博士的指导下进行研究。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进行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、造血和衰老领域的领导者。赞助者和导师将与候选人密切互动，指导其科学和专业发展。最终，该计划将促进候选人成为癌症和衰老独立研究者的目标。

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.