Molecular analysis of hyaluronan and CD44

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你的身体。巨噬细胞是一种免疫细胞，专门用于修复损伤和保护组织免受疾病的侵害。在肺中，肺泡巨噬细胞生活在空气-肺界面的独特环境中，在那里它们保护免受损害和空气传播的疾病。这种环境指导这些巨噬细胞成为能够自我更新的长寿细胞，具有肺表面活性物质周转和空气传播病原体免疫监视的专门功能。它们的独特特征之一是能够结合基质组分透明质酸，一种大的吸水分子。我们已经发现，这种基质-巨噬细胞相互作用促进了它们的存活。在这个建议中，我们将研究透明质酸如何支持肺泡巨噬细胞的生存和功能。我们将检查肺泡巨噬细胞上透明质酸受体CD 44的分子特征，以确定是什么使其能够与透明质酸结合，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，以及哪些细胞产生和分泌它，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肺泡巨噬细胞在其自然环境中，在气道。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。这将提供基本知识和新的见解，了解这种惰性糖分子，透明质酸如何为巨噬细胞提供支持性利基和信号，以促进其在这种环境中的生存。它将表征HA的形式和大小，最好地促进这一功能，并将填补我们知识中的一个重要空白。这些知识将使人工细胞基质的知情开发，旨在促进细胞的存活和寿命。这项工作还具有潜在的意义，超越了巨噬细胞在肺中的存活，因为透明质酸存在于许多组织中，促进长期细胞存活是衰老过程的基础。这项研究将有助于免疫学家，生物学家，生物药理学家和生物工程师，他们可以使用新信息来设计新的应用程序并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。

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.