Establishment of Long-Range Tissue Polarity in the Mammalian Epidermis

描述(申请人提供)：细胞如何组装成复杂的排列，使组织具有特殊的功能，这是生物学中的一个基本问题。为了进行适当的组织组装，细胞的自组织特性必须与远程信号相协调，这些信号将组织组织到体内的正确方向或极性。尽管使用遗传模型生物进行了广泛的研究，但这些远程极化信号的身份仍然未知。随着再生医学领域朝着从多能干细胞生成任何细胞类型的方向发展，发现成人组织适当的三维组织所需的远程信号将是至关重要的。组织极性或平面细胞极性(PCP)是指全球范围内细胞在上皮平面上的集体极化，PCP的遗传破坏会导致严重的发育障碍，如神经管缺陷、囊性肾病、听力损失、纤毛疾病和心脏缺陷。虽然跨物种保存的一组核心PCP基因负责在短距离内从一个细胞传递到另一个细胞的方向信号，但在长距离下，是什么使全球的极性偏向于特定的方向尚不清楚。一种可能性是，在整个组织中以浓度梯度表达的分泌或细胞外信号可能提供全球极化线索。或者，极化细胞与其底物之间的物理相互作用，或在形态发生过程中施加的机械力，可能导致细胞极性的整体排列。识别远距离极化信号的来源将解决极性领域中的一个长期存在的问题，并深刻影响组织工程领域。这项提议的目标是确定协调远程组织极性的分子和物理线索，并破译细胞如何对这些定向线索做出不对称重组。利用哺乳动物皮肤，自然界中最显著的极化组织之一，将结合基因组学、蛋白质组学、成像、遗传学和生物物理方法：(1)确定分级定向线索如何在表皮中偏向组织极性；(2)破译外力在建立远程组织极性中的作用；以及(3)阐明细胞响应定向线索而极化的机制。下一步是确定指导组织的适当三维组织的指导性线索 向体外工程功能器官迈进。最终，识别控制正常组织发育的途径将有助于理解这些途径的不当调控如何导致发育缺陷和成人增殖性疾病。

DESCRIPTION (provided by applicant): How cells assemble into complex arrangements that enable the specialized function of a tissue is a fundamental question in biology. For proper tissue assembly to occur, self-organization properties of cells must be coordinated with long-range signals that organize a tissue into the correct orientation, or polarity, within the body. Despite extensive research using genetic model organisms, the identity of these long-range polarizing signals remains unknown. As the field of regenerative medicine advances towards generating any cell type from multipotent stem cells, the discovery of long-range signals required for the proper three-dimensional organization of adult tissues will be essential. Tissue polarity or planar cell polarity (PCP) refers to the collective polarization of cells globally alon the epithelial plane, and genetic disruption of PCP results in severe developmental disorders such as neural tube defects, cystic kidney disease, hearing loss, ciliopathies, and heart defects. While a core set of PCP genes conserved across species is responsible for communicating directional signals from cell to cell over short distances, what biases polarity globally toward a particular direction over long distances is unknown. One possibility is that a secreted or extracellular signal expressed in a concentration gradient across a tissue could provide a global polarizing cue. Alternatively, physical interactions between polarizing cells and their underlying substratum, or mechanical forces exerted during morphogenesis could lead to global alignment of cell polarity. Identifying the source of long-range polarizing signals will solve a long-standin problem in the polarity field and profoundly impact the field of tissue engineering. The goal of this proposal is to identify the molecular and physical cues that orchestrate long-range tissue polarity and to decipher how cells asymmetrically reorganize in response to these directional cues. Using mammalian skin, one of the most strikingly polarized tissues in nature, a combination of genomic, proteomic, imaging, genetic, and biophysical approaches will be employed to: (1) Determine how graded directional cues bias tissue polarity in the epidermis; (2) Decipher the role of external forces in establishing long-range tissue polarity; and (3) Elucidate the mechanisms by which cells polarize in response to directional cues. Identifying the instructive cues that direct the proper three-dimensional organization of a tissue is the next step towards engineering functional organs in vitro. Ultimately, identification of the pathways controlling normal tissue development will help to understand how misregulation of these pathways leads to developmental defects and adult proliferative disorders.