Molecular analysis of hyaluronan and CD44

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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.