Decoupling the Mechanobiology of Neutrophil Extracellular Traps (NETs) in Tumor Metastasis

解耦肿瘤转移中中性粒细胞胞外陷阱（NET）的力学生物学

• 批准号: 10204048
• 负责人: Arvind Chandrasekaran
• 金额: $ 14.4万
• 依托单位: NORTH CAROLINA AGRI & TECH ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204048
• 关键词: 3-Dimensional; Affect; Apoptosis; Autoimmune Diseases; Automobile Driving; Binding; Biological; Biomedical Engineering; Cell physiology; Cells; Characteristics; Chromatin; Chronic; Clinical; Collagen; Communicable Diseases; Comprehension; Computer Models; DNA; Development; Disease; Disease Progression; E-Cadherin; Epithelial; Extracellular Matrix; Fibroblasts; Goals; Histones; Infection; Inflammation; Innate Immune System; Internet; Invaded; Lead; Leukocytes; Malignant Neoplasms; Measurement; Measures; Mechanics; Mediating; Mesenchymal; N-Cadherin; Neoplasm Metastasis; Nuclear; Pathogenesis; Pathologic; Pathway interactions; Phenotype; Physiological; Population; Porosity; Process; Proteins; Regulation; Research; Rheology; Signal Pathway; Signal Transduction; Structure; TWIST1 gene; Testing; Therapeutic Intervention; Tight Junctions; Tissues; Traction; Translational Research; Tumor Cell Invasion; Vimentin; cell motility; cell stroma; cell type; epithelial to mesenchymal transition; extracellular; in silico; innovation; malignant state; mechanical properties; mechanotransduction; migration; neoplastic cell; neutrophil; novel; response; small hairpin RNA; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression

Arvind Chandrasekaran Abstract Mechanical rigidity of a tumor microenvironment (TME) and the surrounding stroma is an important physical parameter that affects cellular functions. Increased Extracellular Matrix (ECM) stiffness is beginning to be considered as a driving factor in tumor initiation, contributing significantly in mediating the transition from dormant to malignant states. However, understanding of the initial mechanisms leading to the pre-pathological amplification in matrix rigidity is still evolving. Neutrophils form the most abundant cell population of the innate immune system, representing 50– 60% of circulating white blood cells and are the first line of defense during inflammation and infection. Under certain conditions, activated neutrophils undergo a form of programmed cell death by releasing decondensed chromatin, histones and DNA into their surrounding ECM, forming three- dimensional protein web structures called Neutrophil Extracellular Traps (NETs). Recent evidences suggest that NETs that are formed around a tumor could be directly associated with tumor metastasis progression. However, the exact mechanisms and the signaling pathways of NETs interactions with the tumor cells and the stroma are still under research. The primary objective of this project proposal is to decipher the mechanobiological implications of NETs, i.e regulation of the mechanical properties of the tissues (such as stiffness and porosity) due to the formation of NETs, specifically in the context of tumor metastasis. The fundamental hypothesis of this proposal is that NETs accumulating around a tumor bind to the proteins present in the ECM, and stiffen the matrix sufficiently enough to induce downstream biological effects related to tumor growth and invasion. The long-term goal of this project is to understand the mechanobiological organization and regulation of NETs in disease processes. A better comprehension of this concept could have paradigm-shifting implications with respect to the development of suitable therapeutic interventions, not just within the context of tumor metastasis but also towards the pathogenesis of other infectious and autoimmune diseases.

Arvind Chandrasekaran 抽象的 肿瘤微觉（TME）和周围的基质的机械严重性是重要的 影响细胞功能的物理参数。 开始被认为是肿瘤启动的驱动因素，在 介导从休眠状态到恶性状态的过渡。 机制导致基质固定过程中的细胞病理学扩增仍然是进化。 中性粒细胞构成先天免疫系统中最丰富的细胞群，代表50- 60％的循环白细胞，是炎症期间的第一道防线 感染。 通过将解剖的染色质，组蛋白和DNA释放到周围的ECM中，形成三个 尺寸蛋白质的结构称为中性粒细胞外陷阱（NETS） 建议在肿瘤周围形成的网可能与肿瘤直接相关 但是，转移的进展。 与肿瘤细胞和基质的相互作用仍在研究中。 这对破门的主要目的是解密机械生物学的影响 网络，即对组织机械性能的调节（例如刚度和波动性） 网络的形成，特别是在肿瘤转移的背景下 该提议的是，围绕肿瘤围绕ECM中蛋白质的净获得的网络， 并加强了足够的足够加强到足以诱导与肿瘤有关的下游生物学作用 增长和发明。 疾病过程中网的组织和调节。 在适当治疗的发展方面可能具有范式转移的含义 Intertutututntints不仅在肿瘤转移的控制范围内，而且在 其他感染和自身免疫性疾病。