Much of what we know about mammalian biology we have learned from the mouse. However, improvements to human health will ultimately require a better understanding of the integrative biology of human, rather than mouse, tissues. Our understanding of human biology is limited because no experimentally tractable system is available to study human cells in the context of the complex cellular interactions that are characteristic of tissues in vivo. This proposal addresses this unmet need by proposing the synthesis of the most structurally complex and detailed model of a human tissue to date. We will take a combined top-down and bottom-up approach toward this goal, using modular chemical tools to control the spatial organization of multiple cell types in a 3D tissue. We will focus on te mammary gland as the target organ due to its unique developmental biology, relevance to human disease, and important structural differences when compared to model mammalian organisms (Parmar and Cunha, 2004). Our efforts will also be facilitated by a plethora of commonly available and renewable cell sources derived from human tissues that are unique to the mammary gland. Completion of our efforts will provide a revolutionary in vitro model for studying the biology of human tissues and for testing therapeutics. In addition, our fundamentally synthetic approach will force us to challenge commonly held assumptions about the organization and function of human tissues, and will thereby reveal new and exciting biology in the process. The modular synthetic strategies perfected in the course of this proposal will be applicable to many other human tissues, maximizing the impact of this work to the broader biomedical community.
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