Biomechanical Mechanisms Underlying Pathologic Hepatic Stellate Cell Behavior in Liver Fibrosis

肝纤维化中肝星状细胞病理行为的生物力学机制

• 批准号: 10538260
• 负责人: Vivian Zhang
• 金额: $ 4.23万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538260
• 关键词: Address; Adopted; Affect; Ascites; Autoimmune; Autoimmune Diseases; Automobile Driving; Behavior; Biochemical; Biocompatible Materials; Biomechanics; Biomimetics; Cell Differentiation process; Cells; Cessation of life; Characteristics; Chemistry; Cirrhosis; Clinical; Cues; Cytokine Signaling; Disease; Dose; Encephalopathies; Environment; Etiology; Exhibits; Exposure to; Extracellular Matrix; Extrahepatic; Fibrosis; Genotype; Goals; Hepatic Stellate Cell; Hepatitis B Therapy; Hepatitis C; Hospitals; Hybrids; Hydrogels; In Vitro; Injury; Instruction; Knowledge; Light; Literature; Liver; Liver Fibrosis; Liver diseases; Liver parenchyma; Location; Malignant Neoplasms; Mechanics; Mediator of activation protein; Memory; Metabolic Diseases; Molecular; Nature; Nuclear Translocation; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Patients; Phenotype; Portal Hypertension; Predisposition; Primary carcinoma of the liver cells; Process; Property; Relaxation; Research; Risk; Role; Side; Signal Transduction; Stress; Structure-Activity Relationship; System; Therapeutic Intervention; Time; Tissues; Training Activity; Universities; Virus Diseases; Visible Radiation; antifibrotic treatment; base; biomarker signature; burden of illness; cell behavior; chronic liver disease; curative treatments; ethylene glycol; experience; fibrogenesis; in vivo; insight; interest; mechanical properties; mechanical signal; mechanotransduction; migration; nonalcoholic steatohepatitis; novel; patient population; response; simulation; spatiotemporal; stellate cell; targeted treatment; therapeutic development; transdifferentiation; wound healing

PROJECT SUMMARY The unregulated activation of hepatic stellate cells is a key step in the pathogenesis of liver fibrosis, a condition which arises from multiple etiologies including viral infections, autoimmune diseases, metabolic disorders, and toxic insults. When activated, stellate cells become myofibroblastic and adopt wound healing functions. Cirrhosis, the most advanced stage of fibrosis, is associated with severe extrahepatic complications and a lifetime increased risk for hepatocellular carcinoma. Fibrosis was once thought to be a unidirectional, irreversible condition, but recent advances in curative treatment for hepatitis B and C have demonstrated that fibrosis is able to regress. Therefore, effective antifibrotic therapies are in high demand to treat all stages of fibrosis from any etiology. A promising approach is to inhibit the many functions of the activated stellate cell, or the activation process itself, since these steps are central to driving disease pathogenesis. Like all cells, activated stellate cells respond to cues delivered by their surrounding extracellular matrix (ECM). Some of these cues are biochemical in nature. However, the mechanical properties of the ECM are also instructive and provide signals that have profound effects on cell differentiation, migration, remodeling, and tissue organization. The liver possesses two mechanical properties of notable interest: stiffness, the extent to which an object resists deformation to an applied force, and stress relaxation, the ability to dissipate energy from an applied force. An understanding of how stiffness and stress relaxation act independently and synergistically to affect activated hepatic stellate cells may reveal previously unexplored opportunities for therapeutic development. The objectives of the proposed research are therefore to modulate the behavior of hepatic stellate cells by tuning matrix mechanical properties in a spatiotemporally precise manner. We have developed photoresponsive poly(ethylene glycol)/liver ECM hybrid hydrogels with tunable stress relaxation that can be reversibly stiffened with visible light. The Specific Aims of the proposed research are to (1) elucidate the independent role of stress relaxation on hepatic stellate cell mechanical memory and (2) assess hepatic stellate cell durotactic migratory capacity as a function of stress relaxation. In addition to functional readouts of healthy and diseased cell phenotypes, we will use established metrics for cellular mechanosensing, such as YAP nuclear translocation, to develop clear structure-function relationships between ECM mechanics, mechanosensing, and cell behavior. The anticipated product of this research is a causal understanding of the response of stellate cells to mechanical signals. This research will be a collaborative effort between Northwestern University’s Department of Chemistry, Northwestern Memorial Hospital, and external collaborators. In carrying out the proposed Aims and associated training activities, I will develop a unique skillset that allows me to address biomedical problems using materials chemistry as a means of accelerating translational scientific discovery.

项目概要 肝星状细胞的不受调节的激活是肝纤维化发病机制的关键步骤，肝纤维化是一种疾病 由多种病因引起，包括病毒感染、自身免疫性疾病、代谢紊乱和 有毒的侮辱。当被激活时，星状细胞变成肌纤维母细胞并具有伤口愈合功能。肝硬化， 纤维化的最晚期阶段，与严重的肝外并发症和终生相关 肝细胞癌的风险增加。纤维化曾经被认为是单向的、不可逆转的 但乙型肝炎和丙型肝炎治疗的最新进展表明，纤维化能够 回归。因此，迫切需要有效的抗纤维化疗法来治疗任何阶段的纤维化。 病因学。一种有前途的方法是抑制激活的星状细胞的许多功能，或激活 过程本身，因为这些步骤是驱动疾病发病机制的核心。 与所有细胞一样，激活的星状细胞对其周围细胞外基质 (ECM) 传递的信号做出反应。 其中一些线索本质上是生化的。然而，ECM 的机械性能也 具有指导性并提供对细胞分化、迁移、重塑和组织产生深远影响的信号 组织。肝脏具有两个值得注意的机械特性：硬度，即肝脏承受​​压力的程度。 物体抵抗所施加的力的变形，以及应力松弛，即耗散来自物体的能量的能力 施加的力。了解刚度和应力松弛如何独立和协同作用 影响活化的肝星状细胞可能揭示以前未探索的治疗机会 发展。因此，拟议研究的目标是调节肝星状细胞的行为 通过以时空精确的方式调整基质机械特性来调节细胞。我们开发了 具有可调节应力松弛的光响应聚乙二醇/肝脏 ECM 混合水凝胶 可见光可逆硬化。拟议研究的具体目标是（1）阐明 应力松弛对肝星状细胞机械记忆的独立作用和（2）评估肝星状细胞 细胞杜罗定向迁移能力作为应力松弛的函数。除了健康的功能读数外 和患病细胞表型，我们将使用细胞机械传感的既定指标，例如 YAP 核 易位，以在 ECM 力学、机械传感和 细胞行为。这项研究的预期成果是对星状细胞反应的因果理解 到机械信号。这项研究将是西北大学各系之间的合作成果 西北纪念医院化学系和外部合作者。在实现拟议目标时 和相关的培训活动，我将发展一套独特的技能，使我能够解决生物医学问题 使用材料化学作为加速转化科学发现的手段。