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CAREER: Mechanically dynamic and viscoelastic hydrogels as tools for studying fibroblast epigenetic memory

职业：机械动力学和粘弹性水凝胶作为研究成纤维细胞表观遗传记忆的工具

基本信息

批准号：
2046592
负责人：
Steven Caliari
金额：
$ 57.91万
依托单位：
University of Virginia Main Campus
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2046592&HistoricalAwards=false
关键词：
CAREER Mechanically dynamic viscoelastic hydrogels

项目摘要

Non-technical Summary:This project will develop three-dimensional biomaterial models of tissue to better understand how tissue mechanics control persistent scarring, or fibrosis. This is an important societal challenge since fibrosis is a significant contributing factor to nearly half of the overall deaths in the developed world. Biomaterials called hydrogels, or water-swollen polymer networks like contact lenses, will be used to create models matching normal and scarred tissue mechanics. Fibroblasts, the primary cells that drive fibrosis, will be encapsulated in hydrogels that can change their mechanics upon controlled exposure to light. This platform will be used to make tissue models with patterned and reversible mechanical properties mimicking the irregular progression of fibrosis. Careful control of the mechanical signals presented to cells will enable improved fundamental understanding of how these signals are interpreted and “remembered” during fibrosis. This project will also include educational and outreach objectives where the overarching goal is to recruit, mentor, and empower students at all levels from underrepresented backgrounds on the design of biomaterial-based cell culture models.Technical Summary:Tissues undergo dynamic mechanical changes during diverse biological processes including development, disease progression, and remodeling. There is tremendous interest in understanding how these dynamic mechanical cues are sensed and integrated to direct cell behaviors in vivo. Unfortunately, mechanistic studies are complicated by the myriad cells, extracellular matrix (ECM) constituents, and signaling moieties at play. Therefore, there is a significant and unmet need for in vitro biomaterial models that deconstruct this complexity and enable systematic investigation of environmental regulators of cell fate. This proposal will address this critical challenge through the development of a 3D viscoelastic hyaluronic acid (HA) hydrogel platform that permits both dynamic stiffening and softening in the presence of encapsulated cells through the use of orthogonal photochemical reactions. The proposed hydrogel system will be used to study how fibroblasts form mechanical memories during activation into myofibroblasts that drive the pathological scarring process known as fibrosis. While the signaling mechanisms underlying mechanical memory are poorly understood, there is growing evidence that epigenetics (changes in gene function that do not involve alteration in DNA sequence like histone modification and DNA methylation) are prominently involved. The research objectives of this proposal are to develop 3D viscoelastic hydrogels with either 1) uniform stiffening, 2) patterned stiffening, or 3) patterned, reversible stiffening as tools to study the epigenetic regulation of fibroblast mechanical memory. Notable milestones will include photochemical cycling of mechanics from normal to fibrotic levels (stiffening) and back to normal (softening) and spatiotemporal control of hydrogel mechanics using photopatterning to mimic the heterogeneous development of fibrosis. This proposal integrates the PI’s research activities in biomaterials engineering with educational and outreach initiatives focused on mentoring and empowering underrepresented groups in STEM. Together, these efforts will enable the establishment of a laboratory program that designs biomaterial cellular microenvironments to investigate a range of fundamental bioengineering challenges while inspiring future generations of creative, rigorous, and ethical scientists.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.

非技术总结：该项目将开发组织的三维生物材料模型，以更好地了解组织力学如何控制持续性疤痕或纤维化。这是一项重要的社会挑战，因为在发达国家，纤维化是造成近一半总死亡的一个重要因素。被称为水凝胶的生物材料，或者像隐形眼镜一样的水膨胀聚合物网络，将被用于创建与正常和疤痕组织力学相匹配的模型。成纤维细胞是导致纤维化的原代细胞，它将被包裹在水凝胶中，在受控的光照下，水凝胶可以改变它们的机制。该平台将用于制作具有图案和可逆机械特性的组织模型，模拟纤维化的不规则进展。仔细控制提供给细胞的机械信号将有助于提高对这些信号在纤维化过程中如何被解释和“记忆”的基本理解。该项目还将包括教育和推广目标，其总体目标是招募、指导和授权来自未被充分代表背景的各级学生设计基于生物材料的细胞培养模型。技术总结：组织在不同的生物过程中经历动态的力学变化，包括发育、疾病进展和重塑。人们对了解这些动态机械线索如何被感知和整合以指导细胞在体内的行为有着极大的兴趣。不幸的是，机制的研究是复杂的无数细胞，细胞外基质（ECM）成分，并在发挥作用的信号部分。因此，有一个重要的和未满足的体外生物材料模型，解构这种复杂性，使系统的研究细胞命运的环境调节因子。该提案将通过开发3D粘弹性透明质酸（HA）水凝胶平台来解决这一关键挑战，该平台通过使用正交光化学反应，允许在封装细胞存在的情况下动态硬化和软化。提出的水凝胶系统将用于研究成纤维细胞如何在激活成肌成纤维细胞过程中形成机械记忆，从而驱动被称为纤维化的病理性瘢痕过程。虽然机械记忆背后的信号机制尚不清楚，但越来越多的证据表明，表观遗传学（不涉及DNA序列改变的基因功能变化，如组蛋白修饰和DNA甲基化）与机械记忆密切相关。该方案的研究目标是开发具有1)均匀硬化、2)模式硬化或3)模式可逆硬化的三维粘弹性水凝胶，作为研究成纤维细胞机械记忆表观遗传调控的工具。值得注意的里程碑将包括力学从正常到纤维化水平（硬化）和回到正常（软化）的光化学循环，以及利用光模式模拟纤维化异质发展的水凝胶力学的时空控制。该提案将PI在生物材料工程方面的研究活动与教育和推广计划相结合，重点是指导和授权STEM中代表性不足的群体。总之，这些努力将能够建立一个实验室项目，设计生物材料细胞微环境，研究一系列基本的生物工程挑战，同时激励后代的创造性，严谨和道德的科学家。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。