Total synthesis of the human mammary gland

描述(由申请人提供)：我们从老鼠那里学到的关于哺乳动物生物学的大部分知识。然而，人类健康的改善最终将需要更好地理解人类组织的综合生物学，而不是老鼠组织。我们对人类生物学的理解是有限的，因为在体内组织特有的复杂细胞相互作用的背景下，没有实验上容易处理的系统来研究人类细胞。这项建议通过提出合成迄今为止结构最复杂和最详细的人体组织模型来满足这一未得到满足的需求。我们将采取自上而下和自下而上相结合的方法来实现这一目标，使用模块化的化学工具来控制3D组织中多种细胞类型的空间组织。我们将把重点放在乳腺作为目标器官，因为它独特的发育生物学，与人类疾病的相关性，以及与模式哺乳动物相比的重要结构差异(Parmar和Cunha，2004)。我们的努力还将得到来自人体组织的大量常见和可再生的细胞来源的推动，这些组织是乳腺特有的。我们的努力的完成将为研究人体组织生物学和测试疗法提供一个革命性的体外模型。此外，我们从根本上合成的方法将迫使我们挑战关于人类组织组织和功能的普遍假设，从而在这个过程中揭示新的和令人兴奋的生物学。在本提案过程中完善的模块化合成策略将适用于许多其他人类组织，最大限度地扩大这项工作对更广泛的生物医学界的影响。

DESCRIPTION (provided by applicant): 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.