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: 10656257
• 负责人: Vivian Zhang
• 金额: $ 4.32万
• 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/10656257
• 关键词: Acceleration; 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; Elasticity; 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; Knowledge; Light; Literature; Liver; Liver Fibrosis; Liver diseases; Liver parenchyma; Location; Malignant Neoplasms; Mechanics; Mediator; 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; 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; skills; 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.

项目摘要 肝星状细胞的不受调节的激活是肝纤维化发病机理的关键步骤， 由多种病因引起的，包括病毒感染，自身免疫性疾病，代谢性疾病和 有毒侮辱。激活时，星状细胞成为肌纤维细胞并采用伤口愈合功能。肝硬化， 纤维化最先进的阶段与严重的e脚骨外并发症和一生有关 肝细胞癌的风险增加。曾经认为纤维化是单向的，不可逆的 条件，但是丙型肝炎和C治疗治疗的最新进展表明纤维化能够 回归。因此，有效的抗纤维化疗法需求很高，以治疗任何纤维化阶段 病因。一种有希望的方法是抑制活化星状细胞的许多功能，或激活 过程本身，因为这些步骤对于驱动疾病发病机理至关重要。 像所有细胞一样，活化的星状细胞对周围细胞外基质（ECM）传递的提示做出反应。 其中一些提示本质上是生化的。但是，ECM的机械性能也是 具有启发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。肝脏具有引人注目的两个机械特性：刚度 物体将变形恢复到施加的力和压力放松，从而耗散能量从 施加力。了解僵硬和压力放松如何独立和协同作用 受影响的活化的肝星状细胞可能会揭示以前意外的治疗机会 发展。因此，拟议研究的目标是调节肝星状的行为 通过以空间临时精确的方式调整矩阵机械性能。我们已经发展了 具有可调应力松弛的光响应性聚乙二醇）/肝ECM杂化水凝胶 可见光可逆地僵硬。拟议研究的具体目的是（1）阐明 压力放松在肝星状细胞机械记忆中的独立作用和（2）评估肝星状 细胞durotactic迁移能力与应力松弛的关系。除了健康读数 和患病的细胞表型，我们将使用已建立的指标进行细胞机制求解，例如YAP核 易位，发展ECM力学，机械感应和 细胞行为。这项研究的预期产物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系之间的合作努力 化学，西北纪念医院和外部合作者。在执行拟议的目标时 和相关的培训活动，我将开发一个独特的技能，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。