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单元类型的多步骤。在皮肤中，最初受到炎症的炎症，先天免疫反应既有助于防止侵入性生物，也有助于触发炎症反应。接下来是皮肤和表皮细胞的增殖和迁移以关闭伤口。最后，重塑和分化使皮肤正常恢复，从而重新建立了渗透性屏障。维生素D和钙信号传导很可能在这些过程中起作用，尽管这几乎没有在伤口愈合方面进行研究。毛囊凸起的干细胞不仅为毛囊形成，而且为表皮重新上皮化提供了角质形成细胞。这些凸起干细胞的功能由VDR调节。维生素D信号对于表皮中的正常先天免疫反应是必需的。缺乏维生素D受体（VDR）或缺少酶（CY​​P27B1）的小鼠对于产生VDR的关键配体至关重要，1,25二羟基维生素D3（1,25（OH）2d3）未能激活受伤后的固有免疫反应。维生素D信号传导对于调节角质形成细胞增殖和分化也至关重要，这在渗透率屏障的改革中导致。缺乏VDR的小鼠显示出分化标记的表达降低，受伤后的屏障恢复（胶带剥离）。钙是维生素D信号传导调节角质形成细胞中这些过程的机制的关键参与者。像维生素D一样的钙诱导了负责分化的基因，并限制了增殖。钙梯度的重建与受伤后的渗透性屏障的恢复相似（胶带剥离）。钙传感受体（CAR）在这里很关键，其表达受到1,25（OH）2d3的刺激。缺乏汽车的小鼠的先天免疫反应有缺陷，分化标记的表达降低以及受伤后屏障的恢复延迟（胶带剥离）。这些观察结果使我们提出了以下假设。维生素D信号传导通过控制角质形成细胞的增殖和迁移以关闭伤口，并刺激角质形成细胞的区分以通过需要机械改革的机制来改革渗透率，从而调节表皮对伤口的初始炎症反应来调节伤口愈合。我们将通过实现以下目标来检验这一假设。 1。通过评估先天免疫反应，再上皮化率以及其角质形成细胞缺乏VDR的小鼠的分化速率来确定伤口愈合过程中VDR的需求。 2。确定角质形成细胞对伤害的迁移反应中VDR的要求。 3。确定伤口愈合反应中汽车的需求。我们预计我们的发现将导致新疗法可以加速伤害过程，这对我们的军事和退伍军人人口非常重要。 公共卫生相关性： 皮肤为环境中威胁生命的力量提供了主要的障碍。破坏这种障碍会导致体液的损失，并为感染生物提供门户。无法治愈皮肤伤口会导致死亡。因此，至关重要的是，伤口愈合必须有效，同时保护身体在愈合过程中的必需液体和感染的损失。正常的皮肤做得很好。尽管所有生物都需要有效的伤口愈合来进行健康，但退伍军人更有可能患有损害这一过程的医疗状况，无论是烧伤，旧创伤还是糖尿病等医学疾病。在皮肤中这些功能的重要调节剂中，维生素D。维生素D促进了渗透性屏障的形成，防止液体损失以及先天免疫反应，从而防止感染。该项目将评估维生素D信号传导损失对有助于伤口愈合过程的事件的影响。