NSF-BSF: Mechanism of Cuticle Remodeling by Hypoxia

NSF-BSF：缺氧角质层重塑机制

• 批准号: 2308879
• 负责人: Pamela Padilla
• 金额: $ 99.98万
• 依托单位: University of North Texas
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2308879&HistoricalAwards=false
• 关键词: NSF; BSF; Mechanism; Cuticle; Remodeling

The skin is a line of defense between an animal’s interior and the external world, and the structure and function of the skin affects organismal survival. This research investigates how skin structure and function change in response to low oxygen conditions (hypoxia) and will elucidate the underlying biological mechanisms involved. Plastic responses and adaptation to low oxygen are important for understanding respiration and organ stability and function. Moreover, since many animals live in habitats where oxygen levels fluctuate (e.g., in water or underground burrows), this research will help understand how animals survive in challenging ecological niches. This study will test the hypothesis that environmental hypoxia impacts skin permeability and will identify specific molecules and regulatory processes involved, in the nematode Caenorhabditis elegans. Like all animals, C. elegans is covered with skin, and the outermost skin layer is called the cuticle. The cuticle layer is rich with collagen proteins, which are common proteins in the animal kingdom but can be difficult to study because of the many varieties. This project will expand the understanding of collagen and other proteins that regulate collagen structure and function, and the effects on skin structure and function. The researchers will expand their community outreach activities by developing and disseminating podcasts and educational videos that communicate scientific research results and highlight the contributions of individuals from different backgrounds to scientific studies; communications will be made available in four different languages. This collaboration supported by the NSF-BSF program will provide a fruitful platform for research exchanges between students and postdoctoral fellows in the United States and Israel.Skin is a multifunctional organ that serves as a barrier and a communication interface between an animal’s interior and the external environment. A central component of the skin is a three-dimensional network of biological molecules, the extracellular matrix, which is composed of proteins, including many forms of collagen. The objective is to understand how hypoxia affects the structure and function of the skin and decipher the cellular and molecular mechanisms underlying these processes, using C. elegans as a model. Two hypotheses will be tested: (1) the cuticle structure is remodeled and modified in response to hypoxia; (2) Hypoxia Inducible Factor 1 (HIF-1) regulates cuticle structure in a proline-hydroxylation-dependent manner, via post-translational modification. The project will assess the impact hypoxia has on cuticle remodeling using genetic, cellular, and physiological analyses; compare the protein composition of the cuticle in animals exposed to hypoxia or normoxia using targeted proteomics analysis; and determine the mechanism by which HIF-1 controls cuticle remodeling in hypoxia using biochemical, imaging, and genetic approaches. The proposed research could have a transformative impact on the understanding of the role skin plays in adjusting and adapting to fluctuating environmental oxygen levels.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.

皮肤是动物内部和外部世界之间的防线，皮肤的结构和功能影响着生物的生存。这项研究调查了皮肤结构和功能如何在低氧条件下(缺氧)发生变化，并将阐明其潜在的生物学机制。可塑性反应和对低氧的适应对于理解呼吸和器官的稳定性和功能是重要的。此外，由于许多动物生活在氧气水平波动的栖息地(例如，在水中或地下洞穴中)，这项研究将有助于了解动物如何在具有挑战性的生态位中生存。这项研究将检验环境缺氧影响皮肤通透性的假设，并将确定线虫线虫中涉及的特定分子和调节过程。像所有动物一样，线虫身上覆盖着皮肤，最外层的皮肤被称为角质层。角质层富含胶原蛋白，这是动物界常见的蛋白质，但由于种类繁多，研究起来可能很困难。这个项目将扩大对胶原蛋白和其他调节胶原蛋白结构和功能的蛋白质的理解，以及对皮肤结构和功能的影响。研究人员将通过开发和传播播客和教育视频来扩大他们的社区外联活动，传播科学研究成果，并突出不同背景的个人对科学研究的贡献；交流将以四种不同的语言提供。这项由NSF-BSF项目支持的合作将为美国和以色列的学生和博士后研究员之间的研究交流提供一个富有成效的平台。皮肤是一个多功能器官，它是动物内部和外部环境之间的屏障和沟通接口。皮肤的一个中心组成部分是生物分子的三维网络，即细胞外基质，它由蛋白质组成，包括多种形式的胶原。我们的目标是了解缺氧如何影响皮肤的结构和功能，并以线虫为模型，破译这些过程背后的细胞和分子机制。将检验两个假说：(1)角质层结构对低氧的响应被重塑和修饰；(2)低氧诱导因子1(HIF-1)通过翻译后修饰，以依赖于脯氨酸羟化的方式调节角质层结构。该项目将使用遗传学、细胞学和生理学分析来评估缺氧对角质层重塑的影响；使用靶向蛋白质组学分析比较暴露在低氧和常氧下的动物角质层的蛋白质组成；并使用生化、成像和遗传学方法确定HIF-1控制低氧时角质层重塑的机制。这项拟议的研究可能会对理解皮肤在调节和适应环境氧气水平波动中所起的作用产生革命性的影响。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。