Establishment of Long-Range Tissue Polarity in the Mammalian Epidermis

哺乳动物表皮长程组织极性的建立

• 批准号: 9251745
• 负责人: Danelle N Devenport
• 金额: $ 34.55万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251745
• 关键词: Adult; Animal Model; Behavior; Biochemical; Biological Models; Biology; Carrier Proteins; Cell Polarity; Cells; Chemicals; Complex; Cues; Cystic Kidney Diseases; Defect; Development; Dimensions; Disease; Engineering; Epidermis; Epithelial; Epithelial Cells; Gene Expression; Genes; Genetic; Genetic Models; Genetic Transcription; Genomic approach; Genomics; Goals; Heart Abnormalities; Image; In Vitro; Instruction; Invertebrates; Lead; Mechanics; Microfluidics; Molecular; Morphogenesis; Multipotent Stem Cells; Mus; Nature; Neural Tube Closure; Neural Tube Defects; Normal tissue morphology; Organ; Pathway interactions; Patients; Primary Cell Cultures; Property; Proteins; Proteomics; Regenerative Medicine; Research; Role; Signal Transduction; Skin; Source; System; Therapeutic; Time; Tissue Engineering; Tissues; Transgenic Organisms; biophysical techniques; cell type; ciliopathy; developmental disease; extracellular; genetic approach; genome-wide; hearing impairment; imaging approach; mechanical force; planar cell polarity; polarized cell; protein transport; public health relevance; response; self organization

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.

描述（由申请人提供）：细胞如何组装成复杂的排列以实现组织的特殊功能是生物学中的一个基本问题。为了发生正确的组织组装，细胞的自组织特性必须与长程信号相协调，将组织组织成体内正确的方向或极性。尽管使用遗传模型生物体进行了广泛的研究，但这些远程偏振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产生任何细胞类型的方向发展，发现成体组织正确的三维组织所需的远程信号将至关重要。 组织极性或平面细胞极性 (PCP) 是指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、纤毛病和心脏缺陷。虽然跨物种保守的一组核心 PCP 基因负责在短距离内从细胞到细胞传递方向信号，但是什么使全球极性在长距离内偏向特定方向尚不清楚。一种可能性是，在组织中以浓度梯度表达的分泌信号或细胞外信号可以提供全局极化线索。或者，极化细胞与其底层基质之间的物理相互作用，或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。识别长距离偏振信号的来源将解决极性领域长期存在的问题，并对组织工程领域产生深远影响。 该提案的目标是确定协调长范围组织极性的分子和物理线索，并破译细胞如何响应这些方向线索进行不对称重组。使用哺乳动物皮肤（自然界中最引人注目的极化组织之一），将采用基因组学、蛋白质组学、成像、遗传和生物物理方法的组合来：（1）确定分级方向线索如何偏置表皮中的组织极性； (2) 破译外力在建立远程组织极性中的作用； (3) 阐明细胞响应方向提示而极化的机制。 下一步是识别指导组织正确三维组织的指导性线索 致力于体外工程功能器官。最终，识别控制正常组织发育的途径将有助于了解这些途径的失调如何导致发育缺陷和成人增殖性疾病。