HMGCS1调控内质网应激在AML耐药中的作用及机制研究

急性髓系白血病（AML）是一种血液系统常见的恶性肿瘤，其耐药与复发一直是临床所面临的巨大困难。阐明其发生、发展及复发耐药机制，进而寻找新的治疗靶点，具有重要的临床意义。研究表明胆固醇代谢在AML中发挥着重要作用，但其具体机制仍不明确。申请人前期研究发现作为胆固醇代谢通路的上游基因HMGCS1促进AML进展及耐药，在微观上影响内质网应激及线粒体功能。综合前期基础，我们进一步提出假说：HMGCS1可能通过未折叠蛋白应答反应（UPR）调节ERS及内质网与线粒体互作，导致胆固醇代谢重调，从而引起AML的耐药与复发。本课题将利用CRISPR/Cas9、转录组测序、共聚焦显微镜、蛋白组学等生物学技术，从细胞、临床标本和动物模型三个层面，深入地揭示HMGCS1在AML发生中的功能和分子机制，有望为AML的靶向治疗提供新的思路。

As a common hematological malignancy, acute myeloid leukemia（AML）presents a huge difficulty clinically in the aspects of relapse and drug resistance. It’s of great significance to elucidate the mechanisms of AML initiating, developing and relapsing, which could be helpful to discover novel targets. The previous studies indicated cholesterol metabolism was a pivotal player in AML, however, its explicit mechanism is still need to be explored. The applicant had discovered that HMGCS1 accelerates AML developing and drug resistance, and affect endoplasmic reticulum stress (ERS) and mitochondria function on the micro-level. Considering the data from our preliminary research and literature, we hypothesize that HMGCS1 regulates ER-mitochondria interaction through unfold protein reaction (UPR), contributing to AML relapsed and drug resistance. In this project, we will utilize various bio-techniques, such as CRISPR/Cas9, RNA-seq, confocal microscopy, and proteomics, to thoroughly uncover the detailed function and mechanism of HMGCS1 in AML development from the aspects of cell lines, clinical samples and animal models, which might provide a new strategy for AML targeting treatment.