权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigating the molecular and cellular mechanisms of virus-associated hepatocellular carcinoma

研究病毒相关性肝细胞癌的分子和细胞机制

基本信息

批准号：
10651902
负责人：
HSUAN-AN CHEN
金额：
$ 9.83万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651902
关键词：
ATAC-seq Address Advanced Malignant Neoplasm Alleles Antigen Presentation Antigen Presentation Pathway Automobile Driving Biological Phenomena Biology Bypass Cancer Control Cancer Etiology Cancer Patient Cell Aging Cell Communication Cell Cycle Arrest Cell Surface Proteins Cell surface Cells Characteristics Cues Data Development Disease Disease Outbreaks Engineering Environment Epigenetic Process Epithelium Evolution Extrahepatic Genetic Genetic Screening Goals Heterogeneity Immune Immune Evasion Immune system Immunity Immunocompetent Immunocompromised Host Immunodeficient Mouse Immunologic Surveillance Immunology Immunotherapy Impairment Knock-in Mouse Label Laboratories Lesion Ligands Link Liver neoplasms Lung Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Mass Spectrum Analysis Mediating Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Modeling Molecular Mouse Strains Mus Natural Immunity Natural Killer Cells Neoplasm Metastasis Pathway interactions Patients Phase Play Population Heterogeneity Postdoctoral Fellow Predisposition Primary carcinoma of the liver cells Process Proliferating Proteome Regulatory Pathway Research Research Project Grants Role Shapes Side Site TP53 gene Technology Tumor Immunity Tumor Promotion Validation Virus Work adaptive immunity anti-tumor immune response cancer cell cancer therapy cell injury dynamical evolution exhaustion immune clearance immunoregulation in vivo insight molecular dynamics mortality mouse model neoplastic cell novel novel strategies pharmacologic programs restoration senescence single-cell RNA sequencing tool transcriptome sequencing tumor tumor initiation tumor progression tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Cancer development accompanies with the dynamic evolution of immunity, a well-known process termed as immunoediting. However, the underlying mechanisms of the transition between each phase, from immune surveillance to final escape, still remain a lot to discover. This proposal aims to study immunoediting during liver cancer development and progression, with a focus on senescence and metastasis. Senescence is a cell cycle arrest program that limits the expansion of damaged cells and can trigger anti-tumor immunity that leads to their elimination in vivo, serving as a potent barrier to tumorigenesis. However, during tumor initiation, the effective clearance of senescent cells is compromised, warranting a deeper mechanistic understanding of this process. My doctoral research aims to identify critical molecular and cellular players driving anti-tumor immune responses during senescence surveillance triggered by wildtype p53, which is known to modulates cancer immunity. The long-term objective of my thesis project is to define the mechanisms of how senescent cells are susceptible to immune surveillance and how these mechanisms are evaded or bypassed during cancer development and progression. As described in Specific Aims 1.1-1.3, my thesis work has demonstrated that the p53 restoration triggers regression of liver cancers in an immunocompetent host. Using different immunodeficient mouse strains and pharmacological approaches perturbing specific immune compartments, our preliminary data suggests that adaptive immunity plays a key role in senescence surveillance. RNA-seq and mass spectrometry were conducted on both proliferating and senescent tumor cells and revealed several senescence-enriched cell surface factors related to epithelial-immune cell interactions. In Specific Aims 1.4 and 1.5, we aim to functionally interrogate the role of these senescence-induced factors as novel senescence surveillance effectors, with a focus on the regulatory network of antigen presentation pathway and, by exploiting multiplexed in vivo genetic screens established in the Lowe laboratory. My postdoctoral research will continue to study immunoediting with a slight change of the focus from the epithelial-tumor angle to a more immunology-rich perspective, applied to the problem of metastatic immune escape. The proposal aims to investigate the molecular changes of NK cells, shown to have control of early metastasis, after having physical interaction with metastatic cells. During different stages of metastatic colonization, tumor-engaging NK cells are labeled via “SynNotch” technology and will be subjected to single-cell RNA-seq to unveil the NK cell heterogeneity (Specific Aim 2.1) and ATAC-seq to reveal potential epigenetic mechanisms of immune exhaustion with functional perturbation of the altered programs employed (Specific Aim 2.2). The proposed postdoctoral research will increase our mechanistic understanding of NK biology during the metastasis outbreak, paving new paths to harness innate immunity against cancer. In all, these two projects will offer distinct insight into immunoediting, of which the elucidated mechanisms could be exploited for developing novel immunotherapies, jointly with existing ones for more effective cancer control.

项目摘要/摘要： -- 癌症的发展伴随着免疫的最新动态进化过程，这一众所周知的过程被称为免疫。免疫编辑。然而，每个免疫阶段之间的过渡的基本机制是从免疫到免疫。从监测到最终的免疫逃脱，仍有许多有待发现的地方。这项新的提案旨在进一步研究肝脏移植期间的免疫编辑机制。癌症的发生、发展和进展主要集中在细胞的衰老和转移上。衰老是一个完整的细胞周期。逮捕计划称，这一计划限制了受损干细胞的进一步扩张，并可能触发抗肿瘤免疫机制，从而导致患者死亡。在体内，它是阻止肿瘤发生的一个强大的屏障。然而，在肿瘤发生的过程中，它是有效的。对衰老细胞的清除工作受到了很大的影响，这使得我们有理由对这一过程有更深层次的、机械性的理解。我的博士研究生研究团队旨在更好地识别推动抗肿瘤和免疫应答的关键分子因子和细胞因子。在衰老过程中，野生型P53蛋白引发了监测，已知P53蛋白能有效调节癌症和免疫力。从长远来看，我的论文和项目的目的是为了更好地定义衰老的干细胞如何易受感染的机制。免疫监测技术，以及在癌症研究和开发过程中，这些机制是如何被规避或绕过的。进展。正如我在《具体目标》中所描述的那样，我的论文和工作已经证明了P53基因的修复。在一个有免疫能力的宿主体内触发肝癌的消退过程。使用不同的免疫缺陷小鼠品系。而我们的初步研究数据显示，这些药理研究方法不会扰乱特定的免疫器官隔间。适应性免疫在衰老监测中发挥着关键作用。核糖核酸序列分析和质谱学分析。对增殖期肿瘤细胞和衰老肿瘤细胞进行了扫描，发现了几个衰老丰富的肿瘤细胞。表面活性因子与上皮细胞和免疫细胞之间的相互作用有关。在具体的表达目标中，我们的目标是1.4%和1.5%，而我们的目标是在功能上实现。作为一种新颖的衰老和监控效应器，审问这些衰老诱导因子的主要作用，并以一种新的方式。重点是建立抗原递呈和途径调控的网络，主要是通过利用体内和遗传学中的多路基因来实现。 Lowe实验室已经建立了筛查系统。但我的博士后研究团队将继续与我一起学习免疫编辑技术。焦点的一个微小变化是，从上皮细胞-肿瘤角度转向更具免疫学意义的角度，并将其应用于治疗。转移的免疫细胞逃逸的主要问题是，新的提案旨在进一步调查NK细胞的分子生物学变化。在与转移的癌细胞进行了物理上的相互作用之后，显示了对早期转移的控制能力。在不同的治疗过程中。转移和定植的各个阶段，以及与肿瘤相关的NK细胞，都会通过一种名为“SynNotch”的技术被贴上标签，而且也不会被标记出来。受制于一个单细胞RNA-seq计划，将公布第一个NK细胞异质性基因(特定目标为2.1)，并将公布一个ATAC-seq计划。潜在的表观遗传学机制包括免疫衰竭，以及这些改变的程序的功能和扰动。用人单位(具体目标为2.2)。新提出的博士后研究项目将增加我们对博士后工作的机械性理解。在癌症转移和暴发期间，对NK细胞生物学的研究，为进一步利用天然免疫系统预防癌症铺平了新的道路。总而言之，这两个新项目将为免疫编辑提供一个独特的、更深入的见解，其中一个是无法阐明的免疫机制。开发新的人类免疫疗法，与其他现有的生物免疫疗法联合研究，以实现更有效的癌症控制。