Delineating Drivers of Inflammation and Progression in Clonal Hematopoiesis

（请保持文字，不要PDF） 在此输入文本，它是应用程序的新摘要信息。此部分不得超过30行文本。 体细胞白血病相关突变通常发生在造血干细胞和祖细胞（HSPC）中，在没有血液恶性肿瘤的情况下，在衰老过程中。携带这些突变的细胞对骨髓微环境施加压力，破坏正常的造血，无论是关于干细胞内在变化还是微环境扰动，导致克隆扩增，骨髓衰竭和恶性肿瘤的风险。然而，只有一小部分患有CHIP的个体进展到显著的骨髓破坏，并且理解哪些个体将进展仍然是该领域的一个重大差距。使用系统血液学方法，我们提出了一个研究过程，以确定因素，有助于克隆扩增和疾病进展的人类CHIP。我们的长期目标是剖析克隆性髓系疾病的致病机制，并确定逆转疾病进展的治疗靶点。炎症与mTET2 CHIP有着众所周知的关联，但人类的免疫效应和表观遗传水平的原因尚未阐明。这种桥梁资金将使我们能够优化我们的方法，将基因型归因于转录单细胞数据。它将扩大我们的努力，以表征TET2损失的表观遗传反应，并确定沉淀破坏免疫微环境的机制变化。最终，这将直接加强我们的下一次提交这项工作作为一个扩大的研究项目赠款。

(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.