CAREER: Mechanobiology of the Chromatin Remodeling: Implications in Gene Expression, Physiology, and Pathology

这项教师早期职业发展（Career）资助的研究重点是发现细胞核内的基本机制，这可能会极大地提高我们对几种与纤维化相关的退行性疾病的发生和进展的理解。人体内的许多病理状况都与组织中异常的机械环境有关。组织内部需要最佳的机械力来保持细胞的功能和健康。本项目将阐明生物系统的健康或病理机械环境如何通过染色质重塑影响细胞和组织的结构和功能-染色质重塑是细胞核内基因表达的一种新的表观遗传决定因素。这一知识可能为治疗各种退行性疾病提供新的治疗策略，如肺、心、肾、肝、皮肤和血管的纤维化。拟议的研究将通过建立一个基于课程丰富，定量生物学培训和在K-12和STEM中代表性不足的学生中传播生物力学知识的综合教育和推广计划来补充。本项目旨在发现组织水平的张力如何到达核内空间以重塑染色质并确定基因表达。研究人员将利用高分辨率单细胞显微镜、力学知识和先进的图像分析技术来回答力学生物学中的几个突出问题。这项工作将解决：1)机械力如何驱动染色质重塑和基因表达；2)染色质重塑和基因表达的变化如何影响决定组织表型的细胞和组织力学特性；3)如何干预机械-表观遗传通路，使退化的细胞或组织恢复正常。该项目将使PI在染色质机械生物学、表观遗传学和基因表达机制等现有知识的基础上进一步发展，并在机械生物学领域建立长期的职业生涯，以解决生命科学和医学中的各种问题。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) grant supports research focused on discovering a fundamental mechanism inside the cell nucleus that may dramatically improve our understanding of how several degenerative diseases associated with fibrosis occur and progress. Many pathological conditions inside the human body are associated with an abnormal mechanical environment in the tissues. Optimal mechanical force is required inside tissues to keep the cells functional and healthy. This project will elucidate how the biological system's healthy or pathological mechanical environment affects the structure and function of cells and tissues through chromatin remodeling – a novel epigenetic determinant of gene expression inside the cell nucleus. This knowledge can potentially provide new therapeutic strategies to treat a myriad of degenerative diseases, such as fibrosis in the lungs, heart, kidney, liver, skin, and blood vessels. The proposed research will be complemented by establishing a comprehensive educational and outreach program based on curriculum enrichment, quantitative biology training, and disseminating biomechanics knowledge in K-12 and students underrepresented in STEM.This project aims to discover how the tensile force at the tissue level reaches the intranuclear space to remodel the chromatin and determine the gene expression. The researchers will utilize high-resolution single cell microscopy, knowledge of mechanics, and advanced image analysis techniques to answer several outstanding questions in mechanobiology. The work will address: 1) how mechanical forces drive chromatin remodeling and gene expression; 2) how the changes in chromatin remodeling and gene expression affect the cell and tissue mechanical properties that determine the tissue phenotype; and 3) how to intervene in the mechano-epigenetic pathway to restore normalcy in degenerated cells or tissues. This project will allow the PI to advance the boundaries of the existing knowledge in chromatin mechanobiology, epigenetics, and gene expression mechanisms and establish a long-term career in mechanobiology to solve various problems in life sciences and medicine.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.