Project 2 - Cell of origin contributions and vulnerabilities in clonal hematopoiesis

项目 2 - 克隆造血过程中起源细胞的贡献和脆弱性

• 批准号: 10641541
• 负责人: David T Scadden
• 金额: $ 50.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/10641541
• 关键词: Affect; Alleles; Assessment tool; Bar Codes; Bone Marrow; Cell Compartmentation; Cells; Cellular Metabolic Process; Clonal Deletion; Clonal Hematopoietic Stem Cell; DNA Sequence Alteration; Data; Dependence; Diagnosis; Epigenetic Process; Frequencies; Gene Frequency; Genetic Transcription; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Intervention; Mediating; Metabolic; Methods; Molecular; Mutate; Mutation; Pathologic; Pathway interactions; Patient risk; Phenotype; Risk; SOX4 gene; Somatic Mutation; Stress; Testing; Therapeutic Intervention; Validation; genetic variant; in vivo; insight; loss of function; metabolomics; mutant; neoplastic; overexpression; pharmacologic; programs; progression risk; risk mitigation; risk stratification; stem; stem cells; synergism; transcription factor

Project Summary Heterogeneity within the hematopoietic stem cell (HSC) compartment is well defined and we hypothesize may contribute to the wide range of phenotypes emerging from initiation of clonal hematopoiesis (CH). This project will use distinctive tools for assessing cell state in the context of Tet2 deletion to determine how the epigenetic and transcriptional program of the cell of origin affects clonal dominance. These data will provide insight into the mechanisms of clonal dominance and may offer epigenetic signatures indicative of risk for subsequent validation. We will also focus on the metabolic state of dominant CH to define whether features of those cells render them vulnerable to low intensity intervention. Successful accomplishment will guide strategies for selective depletion of aberrant dominant clones.

项目摘要 造血干细胞（HSC）内的异源性是明确的，我们 这一假设可能有助于从克隆形成开始出现广泛的表型。 造血（CH）。这个项目将使用独特的工具来评估细胞的状态， Tet2缺失，以确定起源细胞的表观遗传和转录程序 影响克隆优势度。这些数据将提供深入了解克隆的机制， 显性，并可能提供表观遗传特征，表明后续验证的风险。我们 还将关注占主导地位的CH的代谢状态，以确定这些细胞的特征是否 使他们容易受到低强度干预。成功的成就将引导 异常显性克隆的选择性消除策略。