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Functional consequences of stem and progenitor cell heterogeneity

干细胞和祖细胞异质性的功能后果

基本信息

批准号：
10641537
负责人：
David T Scadden
金额：
$ 261.17万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-07 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641537
关键词：
Address Affect Alleles Area Automobile Driving Behavior Biological Models Biological Process Biology Blood Cells Cells Chemicals Clinical Clone Cells Computer Analysis DNA Sequence Alteration DNMT3a Dependence Epigenetic Process Event Exhibits Funding Gene Expression Regulation Gene Frequency Generations Genetic Genomics Goals Grant Hematopoiesis Hematopoietic Hematopoietic stem cells Heterogeneity Impairment Individual Inflammatory Intervention Investigation Maintenance Metabolic Metabolism Modeling Molecular Molecular Profiling Mutation Outcome Pathogenicity Penetrance Pharmaceutical Preparations Production Research Personnel Resources Risk Signal Transduction Somatic Mutation Stimulus Stress Testing Translations Transplantation Work biomarker development cell behavior comparative disease phenotype epigenome fitness functional outcomes gene regulatory network genetic variant improved in vivo inflammatory milieu innovative technologies insight mutant new technology offspring preclinical evaluation primitive cell progenitor programs response risk prediction stem stem cells therapy development

项目摘要

OVERALL PROJECT SUMMARY Cellular heterogeneity within the hematopoietic stem and progenitor cell (HSPC) pool is an increasingly recognized aspect of normal hematopoiesis. Variability among individual cell clones contributes to these heterogenous cellular states driving diversity of functional outcomes. Each clone bears differences across these functional attributes, which is scripted by the epigenome of each cell. Here, we propose that distinctive clone- specific features are particularly relevant to genetic clonal mutations. Specifically, the cellular and epigenetic state of the clone in which a mutation occurs (the clone-of-origin) will alter cellular outcomes. Further, we hypothesize that clonal diversity may contribute to the highly variable penetrance of a disease phenotype in the context of clonal hematopoiesis (CH). We have assembled four teams of hematopoiesis experts and a pioneering investigator in defining gene regulatory networks utilizing single-cell genomics to address this hypothesis. Using a variety of models, we have evaluated the most common mutations in CH affecting Tet2, Dnmt3a2 and Asxl1. Our motivating hypothesis and these preliminary studies support three focused areas of investigation: 1. Epigenetic states poise the clone-of-origin for transformation by CH mutations, sensitizing cells for clonal dominance; 2. Clones bearing a genetic mutation will exhibit divergent responses to exogenous stimuli further enabling clonal dominance; 3. Metabolic adaptation frequently occur in dominant clones rendering them vulnerable to metabolic drugs to reduce clonal burden. Collectively, these studies will provide a detailed assessment of how hematopoietic clones become dominant, whether molecular signatures can be used to predict clonal behavior in the setting of CH and whether low intensity, metabolism focused strategies can be developed to impair competitively advantaged clones.

总体项目摘要造血干细胞和祖细胞（HSPC）库中的细胞异质性越来越受到关注。正常造血的公认方面。单个细胞克隆之间的变异性有助于这些异质细胞状态驱动功能结果的多样性。每个克隆人都有不同之处，功能属性，这是由每个细胞的表观基因组脚本。在这里，我们提出了一个独特的克隆- 特定特征与遗传克隆突变特别相关。具体来说，细胞和表观遗传发生突变的克隆的状态（原始克隆）将改变细胞结果。我们还假设克隆多样性可能导致了疾病表型的高度可变性，克隆造血（clonal hematopoiesis，CH）我们集结了四支造血专家团队，研究人员利用单细胞基因组学来定义基因调控网络，以解决这一假设。使用在多种模型中，我们评估了CH中影响Tet 2、Dnmt 3a 2和Asxl 1的最常见突变。我们的动机假设和这些初步研究支持三个重点领域的调查：1。表观遗传状态平衡起源克隆以通过CH突变转化，使细胞对克隆敏感。优势; 2.携带基因突变的克隆将进一步表现出对外源刺激的不同反应使克隆优势; 3.代谢适应经常发生在优势无性系中，易受代谢药物的影响，以减少克隆负担。总的来说，这些研究将提供详细的评估造血克隆如何成为主导，分子标记是否可用于预测CH背景下的克隆行为，以及低强度、代谢集中的策略是否可以发展到削弱竞争力的克隆。

项目成果

期刊论文数量（74）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Limited plasticity of monocyte fate and function associated with epigenetic scripting at the level of progenitors.

与祖细胞水平的表观遗传脚本相关的单核细胞命运和功能的可塑性有限。

DOI：
10.1182/blood.2023020257
发表时间：
2023
期刊：
Blood
影响因子：
20.3
作者：
Rhee,Catherine;Scadden,ElizabethW;Wong,LaiPing;Schiroli,Giulia;Mazzola,MichaelC;Chea,PhillipL;Kato,Hiroki;Hoyer,FriedrichF;Mistry,Meeta;Lee,Bum-Kyu;Kim,Jonghwan;Nahrendorf,Matthias;Mansour,MichaelK;Sykes,DavidB;Sadreyev,
通讯作者：
Sadreyev,

An Engineered CRISPR-Cas9 Mouse Line for Simultaneous Readout of Lineage Histories and Gene Expression Profiles in Single Cells.

DOI：
10.1016/j.cell.2020.04.048
发表时间：
2020-06-11
期刊：
Cell
影响因子：
64.5
作者：
Bowling S;Sritharan D;Osorio FG;Nguyen M;Cheung P;Rodriguez-Fraticelli A;Patel S;Yuan WC;Fujiwara Y;Li BE;Orkin SH;Hormoz S;Camargo FD
通讯作者：
Camargo FD

Somatic Mutations Reveal Lineage Relationships and Age-Related Mutagenesis in Human Hematopoiesis.

DOI：
10.1016/j.celrep.2018.11.014
发表时间：
2018-11-27
期刊：
Cell reports
影响因子：
8.8
作者：
Osorio FG;Rosendahl Huber A;Oka R;Verheul M;Patel SH;Hasaart K;de la Fonteijne L;Varela I;Camargo FD;van Boxtel R
通讯作者：
van Boxtel R

Cell Cycle Analysis of Hematopoietic Stem and Progenitor Cells by Multicolor Flow Cytometry.