Channel activity during skin morphogenesis

皮肤形态发生过程中的通道活动

• 批准号: 10156780
• 负责人: ROBERT HSIU-PING CHOW
• 金额: $ 36.3万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10156780
• 关键词: Affect; Anterior; Architecture; Back; Biochemical; Biophysics; Birds; Calcium Channel; Cells; Complex; Consequentialism; Coturnix japonica; Coupled; Dermal; Development; Diffusion; Distal; Embryo; Evaluation; Feathers; Feedback; Fibroblast Growth Factor; Future; Gap Junctions; Gene Activation; Genetic Transcription; Giant Cells; Hair; Ion Channel; Learning; Mammals; Maps; Modeling; Morphogenesis; Natural regeneration; Organ; Paper; Pattern; Pattern Formation; Periodicity; Phenotype; Pigmentation physiologic function; Pigments; Play; Population; Process; Quail; Reaction; Readability; Research; Role; Signal Transduction; Skin; Structure; Study models; Time; Tissues; Translating; Visualization; Work; appendage; bioelectricity; cell behavior; cell motility; electric field; electropotential; gap junction channel; inhibitor/antagonist; insight; melanocyte; millimeter; millisecond; morphogens; mouse model; multidisciplinary; novel; optogenetics; progenitor; programmed cell death protein 1; recruit; regenerative; skin morphogenesis; skin organogenesis; skin regeneration; success; transmission process; vector; wound; wound healing

Our long-term objective is to understand the principles that orchestrate skin morphogenesis in development and wound regeneration. The understanding of biochemical signaling is well advanced. Yet, research into the roles of non-neural bioelectricity lags behind, although evidence for a role of bioelectricity in development, regeneration (McLaughlin and Levin 2018 16; Li et al., 2020 5) and wound healing (Zhao et al. 2012 32) is growing. Our research objective is to study the mechanisms underlying the development and regeneration of skin appendages. In two of our recent research papers, we were inspired to see bioelectricity in action in two tissue patterning processes. First, the orientation of elongating feather buds is regulated by synchronization of oscillating calcium channel activities in bud dermal cells, which is controlled by epidermal Shh signaling (Li et al., 2018 11). Second, the skin frequently shows pigment stripes along the body. The size and spacing of longitudinal pigmentation stripes in Japanese quail was recently shown to be controlled autonomously within melanocyte progenitor populations in a gap junction-dependent manner (Inaba et al., 2019 12). At the time these periodic black/yellow stripes form in embryos, the spacing is in millimeters, a large-scale patterning process that cannot be explained by the classical Turing reaction-diffusion mechanism (patterning in micrometer range). The results led us to think hard about how large-scale tissue architecture is built. While localized signaling centers involving morphogens (e.g., WNT, BMP, FGF) were shown to initiate periodic patterning of feather/hair buds, some unidentified mechanism capable of spanning large distances dynamically must work together to transduce the information over the long-distance scale (Inaba and Chuong, 2019 15). Bioelectricity work here provides a clue. Thus, we organized a multi-disciplinary team to analyze the mechanisms on how biochemical and bioelectric signals integrate to achieve the large-scale tissue patterning. We hypothesize, among other possibilities, transient bioelectrical signaling across gap-junction-coupled cell collectives may allow rapid, long-distance signaling with minimal decrement. Electropotential gradients are harnessed to propagate signals rapidly over the long distance (millimeters in milliseconds) to regulate intracellular messengers and pattern the much larger morphogenetic field. The developing avian skin explants provide an excellent model because of the quantifiable distinct patterns, planar topology for easier channel activity visualization, electric current perturbation and optogenetic gene activation – not easy in the mouse model. Experimentally, we will first gauge the endogenous bioelectric landscape and evaluate the importance of bioelectricity in these two tissue patterning processes (Aim 1A, 2A). Then we will study how ion channels / gap junctions cross-talk with biochemical signals to achieve tissue patterns (Aim 1B, 2B). The work is likely to produce new findings and insights for future applications to use bioelectricity to benefit wound regeneration.

我们的长期目标是了解在发育过程中协调皮肤形态发生的原理 和伤口再生。对生化信号传导的理解已经非常深入。然而，研究 尽管有证据表明生物电在发育中发挥作用，但非神经生物电的作用仍然滞后， 再生（McLaughlin 和 Levin 2018 16；Li 等人，2020 5）和伤口愈合（Zhao 等人 2012 32） 生长。我们的研究目标是研究发育和再生的机制 皮肤附属器。在我们最近的两篇研究论文中，我们受到启发，看到生物电在两个方面的作用 组织图案化过程。首先，伸长的羽芽的方向是通过同步来调节的。 芽真皮细胞中钙通道的振荡活动，由表皮 Shh 信号传导控制（Li 等 等，2018 11）。其次，身体上的皮肤经常出现色素条纹。尺寸和间距 最近表明，日本鹌鹑的纵向色素沉着条纹是在内部自主控制的 以间隙连接依赖性方式调节黑素细胞祖细胞群（Inaba et al., 2019 12）。当时 这些周期性的黑/黄条纹在胚胎中形成，间距以毫米为单位，是一种大规模的图案 经典图灵反应扩散机制无法解释的过程（模式化） 微米范围）。结果促使我们认真思考如何构建大规模的组织结构。尽管 涉及形态发生素（例如 WNT、BMP、FGF）的局部信号中心被证明会启动周期性 羽毛/发芽的图案，一些能够动态跨越大距离的不明机制 必须共同努力才能在长距离范围内转换信息（Inaba 和 Chuong，2019 15）。 生物电工作在这里提供了线索。因此，我们组织了一个多学科团队来分析 生化和生物电信号如何整合以实现大规模组织图案化的机制。 除其他可能性外，我们假设间隙连接耦合细胞上存在瞬时生物电信号 集体可以允许以最小的衰减进行快速、长距离的信号发送。电势梯度为 利用长距离（毫米或毫秒）快速传播信号来调节 细胞内信使并塑造更大的形态发生场。正在发育的禽类皮肤外植体 由于可量化的不同模式、平面拓扑更容易通道，因此提供了一个出色的模型 活动可视化、电流扰动和光遗传学基因激活——在小鼠中并不容易 模型。在实验上，我们将首先测量内源性生物电景观并评估其重要性 这两个组织图案化过程中的生物电（目标 1A、2A）。然后我们将研究离子通道/ 间隙连接与生化信号串扰以实现组织模式（目标 1B、2B）。这项工作很可能是 为未来利用生物电促进伤口再生的应用提供新的发现和见解。