The Structural Basis of TAM Receptor Oligomerizarion and Co-receptor Interactions

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PROJECT SUMMARY/ABSTRACT TAM receptors are a clinically important and mechanistically under-studied RTK subfamily. These receptors have a vital role in maintaining cellular homeostasis through the clearance of apoptotic cells and control of inflammatory and immune responses. Linked to their important regulatory roles, dysregulation of TAM receptors is implicated in numerous disease states including cardiovascular disease, hereditary blindness, infertility, autoimmune disorders, chronic inflammation and cancer. In addition, TAM receptor mediated signaling pathways can be hijacked by viruses to gain entry into host cells. While there is growing interest in TAM receptors as therapeutic targets, their multiple roles in homeostatic processes create challenges for developing therapeutic strategies. Understanding TAM receptor activation mechanisms is important for further investigation of the potential development of targeted therapies. While these receptors are commonly believed to be activated through classical receptor-induced dimerization, my preliminary work presents the first in-depth study of the biochemistry and suggests that this simplified view may not be applicable to TAM receptors. Importantly, to fully understand how TAMs are activated, I intend to utilize a combination of structural, biophysical and biochemical approaches to investigate TAM oligomerization and cross-talk with other receptors. These studies will guide the development of informed theories of TAM receptor activation and provide important insights that may be used for the development of new therapeutics in cancer and viral and autoimmune diseases. The laboratory of Dr. Kathryn Ferguson at the Yale Cancer Biology Institute provides a supportive and innovative research environment to conduct this research, as well as mentorship that is aimed at improving skills necessary for a transition to independence. With access to a wealth of resources and to leading experts in the approaches proposed in this application, I will gain additional training in advanced microscopy techniques to augment my previous and ongoing training. The combination of specialized training in additional structural and biophysical approaches, mentorship and career development activities led by my mentors and at Yale, participation in UE5 activities and my continued work with the Office of Diversity, Equity and Inclusion at Yale, will prepare me to lead a strong independent research program.