Roles of SIRT1 in normal hematopoietic and leukemic stem cells

SIRT1 在正常造血干细胞和白血病干细胞中的作用

基本信息

批准号：
8811100
负责人：
WENYONG CHEN
金额：
$ 31.37万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811100
关键词：
Address Adult Aging Attenuated Biological Assay Blood Bone Marrow Transplantation CD34 gene Cell Aging Cell Survival Cell physiology Chromatin Structure Chronic Myeloid Leukemia Chronic-Phase Myeloid Leukemia Cytogenetics DNA Damage DNA Repair DNA Sequence Alteration Data Deacetylase Development Disease Disease Progression Epigenetic Process Frequencies G22P1 gene Gene Expression Gene Silencing Genes Genetic Recombination Gleevec Goals Health Hematopoietic Neoplasms Hematopoietic stem cells Human Hypermethylation Imatinib Imatinib mesylate In Vitro Knock-out Knowledge Laboratories Leukemic Hematopoietic Stem Cell Longevity Lower Organism Maintenance Malignant - descriptor Malignant Neoplasms Mammalian Cell Mediating Mission Molecular Mus Mutagenesis Mutation Nonhomologous DNA End Joining Outcome Study Pathogenesis Pathway interactions Patients Play Protein p53 Proteins Relapse Research Resistance Role Stem cells Stream Stress Testing Transplantation Tumor Suppressor Proteins Work base bcr-abl Fusion Proteins biological adaptation to stress cancer genetics cancer prevention cancer stem cell cancer therapy cell age cell growth cellular longevity chemotherapy design disability embryonic stem cell fusion gene improved in vivo inhibitor/antagonist insight knockout gene leukemic stem cell mouse model normal aging novel novel strategies novel therapeutics promoter reconstitution resistance mechanism response small molecule tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding molecular interrelationship between longevity and cancer. The long term goal is to understand how a stress-response gene SIRT1 is involved in regulating mammalian longevity and cancer, and to develop novel strategies for cancer treatment and prevention through modulating the gene. The objective of this application is to determine how SIRT1 regulates hematopoietic stem cell functions during aging and upon malignant transformation. The central hypothesis is that SIRT1 is essential for cellular longevity of normal hematopoietic stem cells during aging and under stress, and promotes survival of chronic myelogenous leukemia (CML) stem cells for chemoresistance. The rationale for the proposed research is that better understanding roles of SIRT1 normal and leukemic stem cells will help design an effective strategy to treat CML, and potentially other blood maligancies, by eradicating leukemic stem cells through modulating SIRT1. Thus, the proposed studies is relevant to the NIH's mission to develop fundamental knowledge that will potentially help to reduce the burdens of human disability. Guided by stong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the role of SIRT1 for normal hematopoietic stem cell functions; 2) Determine the role of SIRT1 for CML stem cell survival and chemoresistance; and 3) Determine how SIRT1 regulates mutagenesis in normal and leukemic stem cells. Under aim 1, the consequence of SIRT1 loss on hematopoietic stem cell frequency, quiescence and reconstitution capacity during aging and in response to DNA damage will be determined using bone marrow transplantation assay. Key SIRT1-mediated molecular pathways for stem cell functions will be deciphered. Under aim 2, CML stem cell survival upon inhibition of SIRT1, by gene knockout or small molecule inhibitor, will be determined. Under aim 3, the impact of SIRT1 loss or inhibition on developing genetic mutations in normal hematopoietic stem cells and CML stem cells will be investigated, and key SIRT1-regulated DNA damage repair pathways in stem cells will be identified. The proposed research is significant, because it is expected to shed insight on how SIRT1 plays a role in stem cell aging and tumorigenesis, and to develop a new strategy to eradicate resistant CML stem cells through modulating SIRT1 functions.

描述（由申请人提供）：在理解长寿与癌症之间的分子相互关系方面存在根本差距。长期目标是了解应激反应基因 SIRT1 如何参与调节哺乳动物的寿命和癌症，并通过调节该基因制定治疗和预防癌症的新策略。本申请的目的是确定 SIRT1 在衰老和恶性转化过程中如何调节造血干细胞功能。核心假设是，SIRT1 对于正常造血干细胞在衰老和压力下的细胞寿命至关重要，并促进慢性粒细胞白血病 (CML) 干细胞的存活以实现化疗耐药。这项研究的基本原理是，更好地了解 SIRT1 正常和白血病干细胞的作用将有助于设计一种有效的策略，通过调节 SIRT1 根除白血病干细胞，从而治疗 CML 和其他潜在的血液恶性肿瘤。因此，拟议的研究与美国国立卫生研究院发展基础知识的使命相关，这些知识将有可能有助于减轻人类残疾的负担。在强有力的初步数据的指导下，这一假设将通过三个具体目标进行检验：1）确定SIRT1对正常造血干细胞功能的作用； 2) 确定SIRT1对于CML干细胞存活和化疗耐药的作用； 3) 确定 SIRT1 如何调节正常和白血病干细胞的诱变。在目标 1 下，将使用骨髓移植测定来确定 SIRT1 丧失对衰老过程中造血干细胞频率、静止和重建能力以及对 DNA 损伤的反应的影响。 SIRT1 介导的干细胞功能的关键分子途径将被破译。在目标 2 下，将确定通过基因敲除或小分子抑制剂抑制 SIRT1 后 CML 干细胞的存活率。在目标3下，将研究SIRT1缺失或抑制对正常造血干细胞和CML干细胞中发生基因突变的影响，并将确定干细胞中SIRT1调节的关键DNA损伤修复途径。这项研究意义重大，因为它有望深入了解 SIRT1 如何在干细胞衰老和肿瘤发生中发挥作用，并开发一种通过调节 SIRT1 功能来根除耐药 CML 干细胞的新策略。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Emerging Roles of SIRT1 in Cancer Drug Resistance.

DOI：
10.1177/1947601912473826
发表时间：
2013-03-01
期刊：
Genes & cancer
影响因子：
0
作者：
Wang, Zhiqiang;Chen, Wenyong
通讯作者：
Chen, Wenyong

Overcoming CML acquired resistance by specific inhibition of Aurora A kinase in the KCL-22 cell model.

DOI：
10.1093/carcin/bgr278
发表时间：
2012-02
期刊：
Carcinogenesis
影响因子：
4.7
作者：
Hongfeng Yuan;Zhiqiang Wang;Hao Zhang;Mendel M. Roth;R. Bhatia;Wen Yong Chen
通讯作者：
Hongfeng Yuan;Zhiqiang Wang;Hao Zhang;Mendel M. Roth;R. Bhatia;Wen Yong Chen

The emerging and diverse roles of sirtuins in cancer: a clinical perspective.