Molecular analysis of hyaluronan and CD44

透明质酸和 CD44 的分子分析

• 批准号: RGPIN-2022-04795
• 负责人: Johnson, Pauline
• 金额: $ 3.5万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761032
• 关键词: Molecular; analysis; hyaluronan; CD44

Our long-term goal is to understand how immune cells interact with their tissue environment to regulate their development and function. Immune cells protect you from disease and repair your body when it gets damaged. Macrophages are a type of immune cell that are specifically designed to repair damage and protect the tissue against disease. In the lung, alveolar macrophages live in the unique environment of the air-lung interface where they protect against damage and air-borne disease. This environment directs these macrophages to become long-lived cells capable of self-renewal with specialized functions in lung surfactant turnover and immunosurveillance of airborne pathogens. One of their unique features is an ability to bind the matrix component, hyaluronan, a large water absorbing molecule. We have found that this matrix-macrophage interaction promotes their survival. In this proposal, we will investigate how hyaluronan supports alveolar macrophage survival and function. We will examine the molecular features of the hyaluronan receptor, CD44, on alveolar macrophages, to determine what enables it to bind to hyaluronan, as most macrophage populations do not bind hyaluronan. We will also determine the size of hyaluronan and which cells make and secrete it, and which cells degrade it. We will determine the signals hyaluronan sends to the macrophage to support survival and longevity. Finally, we will investigate what happens to this interaction when there is lung damage and repair. To answer these questions we will use an animal model to examine alveolar macrophages in their natural environment, in the airways. We will employ cellular and molecular approaches and use cutting edge technologies such as RNA sequencing and multi-color flow cytometry. This will provide fundamental knowledge and new insights into how this inert sugar molecule, hyaluronan provides a supportive niche and signals to the macrophage to promote its survival in this environment. It will characterize the form and size of HA that best promotes this function and will fill an important gap in our knowledge. This knowledge will enable the informed development of artificial cell matrices designed to promote cell survival and longevity. This work also has potential significance beyond macrophage survival in the lung, as hyaluronan is present in many tissues, and promoting long-term cell survival is fundamental to the aging process. This research will be of use to immunologists, biologists, biophysicists and bio-engineers who can use the new information to design new applications and develop new technologies that promote cell-survival and tissue regeneration. We will train highly qualified personnel in innovative thinking and inventive scientific discovery, and generate new knowledge that will benefit the Canadian and International scientific community.

我们的长期目标是了解免疫细胞如何与其组织环境相互作用以调节其发育和功能。免疫细胞保护你免受疾病的侵害，并在身体受损时修复它。巨噬细胞是一种专门用于修复损伤和保护组织免受疾病侵害的免疫细胞。在肺中，肺泡巨噬细胞生活在独特的空气-肺界面环境中，在那里它们可以防止损伤和空气传播的疾病。这种环境引导这些巨噬细胞成为具有自我更新能力的长寿细胞，具有肺表面活性物质转换和空气传播病原体免疫监视的专门功能。它们的一个独特特征是能够结合基质成分透明质酸，一种大的吸水分子。我们发现这种基质-巨噬细胞相互作用促进了它们的存活。在这个提议中，我们将研究透明质酸如何支持肺泡巨噬细胞的存活和功能。我们将检查肺泡巨噬细胞上透明质酸受体CD44的分子特征，以确定是什么使它与透明质酸结合，因为大多数巨噬细胞群体不结合透明质酸。我们还将确定透明质酸的大小以及哪些细胞制造和分泌它，哪些细胞降解它。我们将确定透明质酸发送给巨噬细胞的信号，以支持生存和长寿。最后，我们将研究当存在肺损伤和修复时，这种相互作用会发生什么。为了回答这些问题，我们将使用动物模型来检查气道中自然环境中的肺泡巨噬细胞。我们将采用细胞和分子方法，并使用尖端技术，如RNA测序和多色流式细胞术。这将为了解这种惰性糖分子透明质酸如何为巨噬细胞提供支持的生态位和信号以促进其在这种环境中的生存提供基础知识和新的见解。它将描述最能促进这一功能的HA的形式和大小，并将填补我们知识中的一个重要空白。这一知识将使旨在促进细胞存活和寿命的人工细胞基质的知情发展成为可能。由于透明质酸存在于许多组织中，促进细胞的长期存活是衰老过程的基础，因此这项工作也具有潜在的意义，而不仅仅是肺中的巨噬细胞存活。这项研究将对免疫学家、生物学家、生物物理学家和生物工程师有用，他们可以利用这些新信息来设计新的应用和开发促进细胞存活和组织再生的新技术。我们将培养具有创新思维和创造性科学发现的高素质人才，并产生有利于加拿大和国际科学界的新知识。