Role of vitamin D and calcium signaling in wound healing

维生素 D 和钙信号在伤口愈合中的作用

• 批准号: 8257062
• 负责人: DANIEL David BIKLE
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257062
• 关键词: Acute; Attention; Burn injury; Calcium; Calcium Signaling; Calcium-Sensing Receptors; Cells; Cessation of life; Dermal; Diabetes Mellitus; Differentiation Antigens; Disease; Environment; Enzymes; Epidermis; Event; Failure; Genes; Hair follicle structure; Healed; Health; Immune response; Immune system; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory Response; Knockout Mice; Lead; Life; Ligands; Liquid substance; Medical; Military Personnel; Mus; Organism; Participant; Permeability; Play; Population; Process; Recovery; Regulation; Role; Signal Transduction; Skin; Stem cells; Testing; Time; Trauma; Veterans; Vitamin D; Vitamin D3 Receptor; Wound Healing; cell type; healing; keratinocyte; keratinocyte differentiation; macrophage; migration; public health relevance; response; restoration; wound

DESCRIPTION (provided by applicant): Wound healing is essential for survival. This is a multistep processes involving a number of different cell types. In the skin wounding is followed initially by inflammation, with the innate immune response contributing both to protection against invasive organisms and to triggering the inflammatory response. This is followed by proliferation and migration of dermal and epidermal cells to close the wound. Finally remodeling and differentiation restore the skin to normal, reestablishing the permeability barrier. Vitamin D and calcium signaling most likely play a role in these processes, although this has received little study in wound healing. Stem cells in the bulge of the hair follicle provide keratinocytes not only for hair follicle formation but also for the reepithelialization of the epidermis following wounding. The function of these bulge stem cells is regulated by VDR. Vitamin D signaling is necessary for a normal innate immune response in the epidermis. Mice lacking the vitamin D receptor (VDR) or lacking the enzyme (CYP27B1) critical for producing the key ligand for VDR, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3), fail to activate their innate immune response following wounding. Vitamin D signaling is also critical for regulation of keratinocyte proliferation and differentiation, eventuating in the reformation of the permeability barrier. Mice lacking the VDR show decreased expression of differentiation markers and a retarded barrier recovery after wounding (tape stripping). Calcium is a critical participant in the mechanism by which vitamin D signaling regulates these processes in keratinocytes. Calcium like vitamin D induces the genes responsible for differentiation, and limits proliferation. Reestablishment of the calcium gradient parallels the restoration of the permeability barrier after wounding (tape stripping). The calcium sensing receptor (CaR) is critical here, and its expression is stimulated by 1,25(OH)2D3. Mice lacking the CaR have a defective innate immune response, decreased expression of differentiation markers, and delayed recovery of the barrier after wounding (tape stripping). These observations have led us to the following hypothesis. Vitamin D signaling regulates wound healing by enabling the initial inflammatory response of the epidermis to wounding, by controlling the proliferation and migration of keratinocytes to close the wound, and by stimulating the differentiation of the keratinocytes to reform the permeability barrier through mechanisms requiring the CaR. We will test this hypothesis by achieving the following aims. 1. Determine the requirement for VDR in the wound healing process by assessing the innate immune response, the rate of reepithelialization, and the rate of differentiation in mice lacking VDR in their keratinocytes. 2. Determine the requirement for VDR in the migratory response of keratinocytes to wounding. 3. Determine the requirement for CaR in the wound healing response. We anticipate that our findings will lead to new therapies by which the wounding process can be accelerated, a process of great importance for our Military and Veteran populations. PUBLIC HEALTH RELEVANCE: The skin provides the major barrier to the life threatening forces in the environment. Disrupting this barrier leads to loss of bodily fluids and provides a portal for infectious organisms. Failure to heal skin wounds can lead to death. Therefore, it is essential that wound healing be efficient and at the same time protect the body from both losses of essential fluids and infection during the healing process. The normal skin does this quite well. Although all creatures require efficient wound healing for health, Veterans are more likely to have medical conditions that compromise this process, whether it be burns, old trauma, or medical diseases such as diabetes mellitus. Among the important regulators of these functions in skin is vitamin D. Vitamin D facilitates the formation of the permeability barrier, protecting against losses of fluids, and the innate immune response, protecting against infection. This project will evaluate the impact of loss of vitamin D signaling on events that contribute to the wound healing process.

描述（由申请人提供）： 伤口愈合对于生存至关重要。这是一个涉及多种不同细胞类型的多步骤过程。在皮肤受伤之后，首先会出现炎症，先天免疫反应有助于保护免受入侵生物体的侵害并引发炎症反应。随后真皮和表皮细胞增殖和迁移以闭合伤口。最后重塑和分化使皮肤恢复正常，重建渗透屏障。维生素 D 和钙信号传导很可能在这些过程中发挥作用，尽管这在伤口愈合方面的研究很少。毛囊隆起处的干细胞不仅为毛囊的形成提供角质形成细胞，而且还为受伤后表皮的再上皮化提供作用。这些凸起干细胞的功能受VDR调节。维生素 D 信号传导对于表皮正常的先天免疫反应是必需的。缺乏维生素 D 受体 (VDR) 或缺乏对产生 VDR 关键配体 1,25 二羟基维生素 D3 (1,25(OH)2D3) 至关重要的酶 (CYP27B1) 的小鼠，在受伤后无法激活其先天免疫反应。维生素 D 信号传导对于角质形成细胞增殖和分化的调节也至关重要，最终导致渗透性屏障的重建。缺乏 VDR 的小鼠在受伤（胶带剥离）后表现出分化标记物表达降低和屏障恢复迟缓。钙是维生素 D 信号传导调节角质形成细胞这些过程的机制的关键参与者。钙和维生素 D 一样可以诱导负责分化的基因，并限制增殖。钙梯度的重建与受伤（胶带剥离）后渗透性屏障的恢复平行。钙敏感受体 (CaR) 在此至关重要，其表达受 1,25(OH)2D3 刺激。缺乏 CaR 的小鼠先天免疫反应有缺陷，分化标记物表达减少，受伤（胶带剥离）后屏障恢复延迟。这些观察使我们得出以下假设。维生素 D 信号通过以下方式调节伤口愈合：使表皮对伤口产生初始炎症反应；控制角质形成细胞的增殖和迁移以闭合伤口；以及通过刺激角质形成细胞的分化，通过需要 CaR 的机制来重塑通透性屏障。我们将通过实现以下目标来检验这一假设。 1. 通过评估角质形成细胞中缺乏 VDR 的小鼠的先天免疫反应、再上皮化率和分化率，确定伤口愈合过程中对 VDR 的需求。 2.确定角质形成细胞对受伤的迁移反应中VDR的需要。 3.确定伤口愈合反应中对CaR的需求。我们预计我们的发现将带来新的疗法，从而加速受伤过程，这对我们的军人和退伍军人来说非常重要。 公共卫生相关性： 皮肤是抵御环境中威胁生命的力量的主要屏障。破坏这一屏障会导致体液流失，并为传染性生物体提供入口。皮肤伤口无法愈合可能会导致死亡。因此，伤口必须有效愈合，同时在愈合过程中保护身体免受必需液体的流失和感染。正常皮肤可以很好地做到这一点。尽管所有生物都需要有效的伤口愈合才能保持健康，但退伍军人更有可能患有损害这一过程的健康状况，无论是烧伤、旧伤还是糖尿病等疾病。维生素 D 是皮肤这些功能的重要调节剂之一。维生素 D 促进渗透性屏障的形成，防止液体流失，以及先天免疫反应，防止感染。该项目将评估维生素 D 信号传导缺失对伤口愈合过程的影响。