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

基本信息

批准号：
8306217
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
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306217
关键词：
AML1-ETO fusion protein Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Adult Affect Age Age Factors Aging Animal Model Biology Cancer Biology Cardiovascular system Cell Differentiation process Cell Proliferation Cells Chemicals Chromosomal translocation 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 Outcome Pathogenesis Patients Phenotype RUNX1 gene Research Research Personnel Resistance Role Supervision Survival Rate Testing Therapeutic Toxic effect Transgenic Organisms Treatment outcome Whole Organism Work Zebrafish age group age related chemical genetics genome-wide immune function in vivo insight leukemia malignant phenotype mutant novel novel therapeutics older patient prognostic programs promoter research study response small molecule t(8 21)(q22 q22)therapeutic target tool

项目摘要

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）是老年人普遍存在的致命疾病。与急性淋巴细胞白血病的发病率（所有）在不同年龄段的人群中几乎相同，AML的发病率随着年龄的增长而急剧增加，表明年龄与AML发病机理之间存在很强的关联。拟议的研究旨在（1）确定AML患者中发现的两个常见突变如何促进AML发病机理；（2）确定依赖年龄的因素，这些因素有助于AML发病机理；（3）验证针对AML的潜力，新颖的治疗剂。实验将利用各种独特的斑马鱼模型，从而实现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型生物，因为它高度适合遗传和化学扰动。已经显示出了十多个斑马鱼突变体可以概括人类血液学疾病的特征，表明造血系统在斑马鱼和人类之间高度保守。拟议的研究不仅将为AML发病机理提供新的见解，而且还为使用斑马鱼研究造血系统的衰老奠定了基础。此外，提出的实验将利用我们最近确定的斑马鱼中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对针对AML的更有效和更安全的治疗剂的开发有用。候选人具有癌症和分子生物学的背景，现在试图扩大其科学专业知识，并开发围绕癌症，衰老和化学生物学的研究计划。候选人将在兰德尔·彼得森（Randall Peterson）博士的监督下进行研究。彼得森博士以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而闻名。候选人还组建了一组顾问小组，其中包括癌症，血红素和衰老的领导者。赞助商和顾问将与候选人紧密互动，并指导她进行科学和专业发展。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。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Efficient genome editing in zebrafish using a CRISPR-Cas system.

DOI：
10.1038/nbt.2501
发表时间：
2013-03
期刊：
Nature biotechnology
影响因子：
46.9
作者：
通讯作者：

Targeted gene disruption in somatic zebrafish cells using engineered TALENs.

DOI：
10.1038/nbt.1934
发表时间：
2011-08-05
期刊：
Nature biotechnology
影响因子：
46.9
作者：
通讯作者：

Highly efficient generation of heritable zebrafish gene mutations using homo- and heterodimeric TALENs.

DOI：
10.1093/nar/gks518
发表时间：
2012-09
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Cade L;Reyon D;Hwang WY;Tsai SQ;Patel S;Khayter C;Joung JK;Sander JD;Peterson RT;Yeh JR
通讯作者：
Yeh JR

Heritable and precise zebrafish genome editing using a CRISPR-Cas system.

DOI：
10.1371/journal.pone.0068708
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Hwang WY;Fu Y;Reyon D;Maeder ML;Kaini P;Sander JD;Joung JK;Peterson RT;Yeh JR
通讯作者：
Yeh JR

Zebrafish small molecule screen in reprogramming/cell fate modulation.

斑马鱼小分子筛选重编程/细胞命运调节。