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: 8140652
• 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/8140652
• 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; 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）： 伤口愈合对生存至关重要。这是一个涉及许多不同细胞类型的多步骤过程。在皮肤中，创伤之后最初是炎症，先天免疫应答有助于保护免受入侵生物体的侵害并触发炎症应答。随后是真皮和表皮细胞的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和钙信号最有可能在这些过程中发挥作用，尽管这在伤口愈合中几乎没有得到研究。毛囊隆突中的干细胞不仅为毛囊形成提供角质形成细胞，而且还为创伤后表皮的再上皮化提供角质形成细胞。这些隆突干细胞的功能由VDR调节。维生素D信号传导对于表皮中的正常先天免疫应答是必需的。缺乏维生素D受体（VDR）或缺乏对产生VDR的关键配体1，25二羟基维生素D3（1，25（OH）2D3）至关重要的酶（CYP 27 B1）的小鼠在创伤后不能激活其先天免疫应答。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是至关重要的，最终导致渗透性屏障的重新形成。缺乏VDR的小鼠显示分化标志物的表达降低和创伤后屏障恢复延迟（胶带剥离）。钙是维生素D信号调节角质形成细胞中这些过程的机制的关键参与者。钙如维生素D诱导负责分化的基因，并限制增殖。钙梯度的重建与创伤（胶带剥离）后渗透性屏障的恢复平行。钙敏感受体（CaR）在这里是至关重要的，它的表达受到1，25（OH）2D3的刺激。缺乏CaR的小鼠具有先天性免疫应答缺陷、分化标志物表达降低以及创伤后屏障恢复延迟（胶带剥离）。这些观察使我们得出以下假设。维生素D信号传导通过使表皮对创伤的初始炎症反应成为可能、通过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以通过需要CaR的机制改革渗透性屏障来调节伤口愈合。我们将通过实现以下目标来检验这一假设。1.通过评估角质形成细胞中缺乏VDR的小鼠的先天免疫应答、上皮再生率和分化率，确定伤口愈合过程中对VDR的需求。2.确定在角质形成细胞对创伤的迁移反应中对VDR的需求。3.确定伤口愈合反应中对CaR的要求。我们预计，我们的研究结果将导致新的治疗方法，通过这种方法可以加速创伤过程，这对我们的军队和退伍军人群体非常重要。 公共卫生相关性： 皮肤提供了对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门户。皮肤伤口不愈合可能导致死亡。因此，至关重要的是，伤口愈合是有效的，同时保护身体在愈合过程中免受基本流体的损失和感染。正常的皮肤做得很好。虽然所有的生物都需要有效的伤口愈合的健康，退伍军人更有可能有医疗条件，损害这一进程，无论是烧伤，旧的创伤，或医疗疾病，如糖尿病。皮肤中这些功能的重要调节剂之一是维生素D。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信号丢失对有助于伤口愈合过程的事件的影响。