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.

（请保持言语，不要PDF） 在此处输入文本，这是您应用程序的新摘要信息。本节必须不超过30行文本。 在没有血液学恶性肿瘤的情况下，在造血干细胞和祖细胞（HSPC）中通常发生了体细胞性白血病相关突变。具有这些突变的细胞对骨髓微环境施加压力，破坏了正常的造血性，均在干细胞的固有变化和微环境扰动方面，导致克隆扩张，骨髓衰竭和恶性肿瘤的风险。但是，只有一部分有芯片的个体发展到严重的骨髓破坏，并了解哪些人将进展的人仍然是该领域的显着差距。使用系统血液学方法，我们提出了一项研究课程，以确定有助于克隆扩张和人类芯片疾病进展的因素。我们的长期目标是剖析克隆髓样疾病的致病机制，并确定治疗靶标以逆转疾病的进展。炎症与MTET2芯片有着众多的关联，但是人类的免疫作用和表观遗传水平的原因尚未阐明。该桥梁资金将使我们能够优化将基因型归纳到转录单细胞数据的方法。它将扩大我们的努力来表征对TET2损失的表观遗传反应，并确定导致免疫微环境中断的机械变化。最终，这将直接加强我们作为扩展的研究项目赠款的下一次提交这项工作。