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

描述(申请人提供)：急性髓系白血病(AML)是一种在老年人中流行的致命疾病。不同于急性淋巴细胞白血病(ALL)的发病率在不同年龄段的人群中基本保持不变，AML的发病率随着年龄的增加而急剧增加，这表明年龄与AML的发病机制之间存在很强的相关性。这项拟议的研究旨在(1)确定在AML患者中发现的两种常见突变如何促进AML的发病；(2)确定导致AML发病的年龄相关因素；以及(3)验证潜在的、针对AML的新疗法。这些实验将利用各种独特的斑马鱼模型，使人类癌基因能够诱导表达。斑马鱼已经成为一种强大的脊椎动物模式生物，因为它高度容易受到遗传和化学干扰。十多个斑马鱼突变体被证明概括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。本研究不仅为AML发病机制的研究提供了新的思路，也为利用斑马鱼研究造血系统的衰老奠定了基础。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物。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治疗急性髓细胞白血病的药物。这位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长，并开发一个以癌症、衰老和化学生物学为中心的研究项目。候选人将在兰德尔·彼得森博士的监督下进行这项研究。彼得森博士以将化学遗传工具和斑马鱼发育生物学相结合用于心血管研究的开创性工作而闻名。这位候选人还组建了一个顾问小组，其中包括癌症、造血和老龄化方面的领导人。赞助商和顾问将与候选人密切互动，指导她在科学和专业方面的发展。最终，这项计划将促进候选人成为癌症和老龄化领域的独立调查员的目标。

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.