Project Funding Details

Everyday billions of cells die in the body as part of normal development and homeostasis. Dying cells must be promptly cleared from the body to prevent the development of autoimmune diseases. As cells die, they produce 'find-me'' signals to attract and recruit other cells (phagocytes) that engulf and clear the dying cells. Dying cells also expose 'eat-me'' signals on their surface that are recognized by the phagocytes. This clearance process does not activate the immune system and is critical in preventing inflammation. However, recent studies suggest that under certain conditions, such as chemotherapies, it may be advantageous for the 'find-me'' signals to initiate an immune response, that help in elimination of the tumor. Thus, understanding how the find-me signals are released and the molecular details of this process can be fundamentally useful for treating cancers and removal of cancer cells. In this proposal, we will study the protein pannexin, which is a channel that releases the 'find me'' signals from the inside of dying cells to attract the phagocytes. We wish to address two primary questions. First, how would mice that lack the pannexin protein clear the dying cells, and we wish to use as a model the thymic development of T cells (where 95% of developing cells die and release find-me signals to promote their clearance by phagocytes). Second, we are also interested in the precise steps that lead to 'opening'' of the pannexin channel when the cells die and how these steps are regulated. Our ultimate goal is that by defining the steps in find-me signal release in vitro and in vivo, these insights would help in designing better therapeutics for tumor elimination and autoimmune diseases.

Everyday billions of cells die in the body as part of normal development and homeostasis. Dying cells must be promptly cleared from the body to prevent the development of autoimmune diseases. As cells die, they produce 'find-me'' signals to attract and recruit other cells (phagocytes) that engulf and clear the dying cells. Dying cells also expose 'eat-me'' signals on their surface that are recognized by the phagocytes. This clearance process does not activate the immune system and is critical in preventing inflammation. However, recent studies suggest that under certain conditions, such as chemotherapies, it may be advantageous for the 'find-me'' signals to initiate an immune response, that help in elimination of the tumor. Thus, understanding how the find-me signals are released and the molecular details of this process can be fundamentally useful for treating cancers and removal of cancer cells. In this proposal, we will study the protein pannexin, which is a channel that releases the 'find me'' signals from the inside of dying cells to attract the phagocytes. We wish to address two primary questions. First, how would mice that lack the pannexin protein clear the dying cells, and we wish to use as a model the thymic development of T cells (where 95% of developing cells die and release find-me signals to promote their clearance by phagocytes). Second, we are also interested in the precise steps that lead to 'opening'' of the pannexin channel when the cells die and how these steps are regulated. Our ultimate goal is that by defining the steps in find-me signal release in vitro and in vivo, these insights would help in designing better therapeutics for tumor elimination and autoimmune diseases.