Delineating Drivers of Inflammation and Progression in Clonal Hematopoiesis

描述克隆造血过程中炎症和进展的驱动因素

• 批准号: 10869051
• 负责人: PAUL B FERRELL
• 金额: $ 15万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10869051
• 关键词: ATAC-seq; Age; Aging; Antigen Presentation; Blood; Bone Marrow; Bone marrow failure; Cell physiology; Cells; Chromatin; Clonal Expansion; DNA; DNA Sequence Alteration; DNA sequencing; Data; Data Set; Disease; Disease Progression; ETS2 gene; Enhancers; Epigenetic Process; Event; Functional disorder; Funding; Future; Gene Mutation; Genes; Genetic; Genetic Transcription; Genome; Genotype; Goals; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic stem cells; Howard Temin Award; Human; Hypermethylation; Immune; Immune System Diseases; Immune system; Immunology; Individual; Inflammation; Interleukin-6; Investigation; Lesion; Libraries; Malignant Neoplasms; Methods; Methylation; Molecular; Molecular Profiling; Mus; Mutate; Mutation; Myelogenous; Myeloproliferative disease; Ontology; Pathogenicity; Patients; Population; Qualifying; Radiation; Recommendation; Regulation; Regulon; Reporting; Research Project Grants; Risk; Sampling; Somatic Mutation; Stress; System; Systems Biology; T-Lymphocyte; Techniques; Text; Time; Work; analysis pipeline; blood formation; demethylation; epigenetic regulation; epigenomics; experimental study; feasibility testing; gene regulatory network; human model; leukemia; loss of function; loss of function mutation; monocyte; mouse model; normal aging; peripheral blood; repository; response; single cell analysis; single-cell RNA sequencing; stem cells; therapeutic target; tumor-immune system interactions

(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Somatic, leukemia-associated mutations commonly occur in hematopoietic stem and progenitor cells (HSPC) during aging in the absence of hematologic malignancy. Cells harboring these mutations exert stress on the bone marrow microenvironment, disrupting normal hematopoiesis, both with respect to stem cell intrinsic changes and microenvironmental perturbations, leading to clonal expansion, bone marrow failure, and risk of malignancy. However, only a fraction of individuals with CHIP progress to significant bone marrow disruption and understanding which individuals will progress remains a significant gap in the field. Using a systems hematology approach, we propose a course of study to identify factors that contribute to clonal expansion and disease progression in human CHIP. Our long-term goal is to dissect the pathogenic mechanisms of clonal myeloid disorders and identify therapeutic targets to reverse disease progression. Inflammation has a well-known association with mTET2 CHIP, but the immune effects in humans and causes at the epigenetic levels have not been elucidated. This bridge funding will allow us to optimize our approach to imputing genotype onto transcriptional single cell data. It will expand our effort to characterize the epigenetic responses to TET2 loss and identify mechanistic changes that precipitate a disrupted immune microenvironment. Ultimately, this will directly strengthen our next submission of this work as an expanded research project grant.

（请以 WORD 形式保存，请勿以 PDF 形式保存） 在此处输入文本，该文本是您的应用程序的新摘要信息。此部分的文本长度不得超过 30 行。 在没有血液恶性肿瘤的情况下，衰老过程中造血干细胞和祖细胞（HSPC）通常会发生与白血病相关的体细胞突变。携带这些突变的细胞会对骨髓微环境施加压力，破坏正常的造血功能，无论是干细胞内在变化还是微环境扰动，都会导致克隆扩张、骨髓衰竭和恶性肿瘤风险。然而，只有一小部分患有 CHIP 的个体会出现严重的骨髓破坏，并且了解哪些个体会出现进展仍然是该领域的重大空白。使用系统血液学方法，我们提出了一个研究过程，以确定有助于人类 CHIP 克隆扩张和疾病进展的因素。我们的长期目标是剖析克隆性骨髓疾病的致病机制并确定逆转疾病进展的治疗靶点。众所周知，炎症与 mTET2 CHIP 存在关联，但其对人类的免疫影响以及表观遗传水平的原因尚未阐明。这笔过渡资金将使我们能够优化将基因型归因于转录单细胞数据的方法。它将扩大我们的努力，以表征 TET2 丢失的表观遗传反应，并确定导致免疫微环境破坏的机制变化。最终，这将直接加强我们下一次提交的这项工作作为扩大的研究项目拨款。