STRESS INDUCED SKIN MAST CELL ACTIVATION & VASODILATION

压力引起的皮肤肥大细胞激活

• 批准号: 7315757
• 负责人: THEOHARIS C. THEOHARIDES
• 金额: $ 35.26万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-13 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315757
• 关键词: Adoptive Transfer; Adrenal Glands; Affect; Age; Anxiety; Area; Atopic Dermatitis; Attenuated; Biological Assay; Biopsy; Bone Marrow; Bone Marrow Cells; CRH gene; Cell Degranulation; Cells; Chronic; Chymase; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Dependence; Disease; Dose; Down-Regulation; Equipment and supply inventories; Functional disorder; Glucocorticoids; Goals; Greek; HPSE gene; Histamine Release; Histidine Decarboxylase; Hormone Receptor; Human; In Situ Hybridization; Inflammation; Inflammatory; Knockout Mice; Mediating; Mediator of activation protein; Methods; Mus; Nerve Growth Factor 1; Neurogenic Inflammation; Neuropeptides; Neurotensin; Neurotensin Receptors; Numbers; Pathogenesis; Patients; Population; Protein Overexpression; Psoriasis; Publishing; Qualifying; Questionnaires; Reaction Time; Regulation; Relative (related person); Reporting; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Screening procedure; Serum; Skin; Spinal Ganglia; Stress; Techniques; Technology; Testing; Tissues; Tryptase; Umbilical Cord Blood; Urticaria; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vasodilation; Work; acute stress; base; chemokine; clinically relevant; cytokine; design; hypothalamic-pituitary-adrenal axis; indexing; innovation; keratinocyte; knowledge base; mast cell; mouse model; novel; prevent; progenitor; programs; receptor; receptor expression; reconstitution; research study; response; restraint stress; sex; skin disorder; trait; urocortin

DESCRIPTION (provided by applicant): There is a fundamental gap in our understanding of why skin diseases, such as chronic urticaria and psoriasis, are aggravated by stress. The long-term goal of this research is to define the role of mast cells in inflammatory diseases. The objective of this application is to identify the contribution of the corticotropin-releasing hormone (CRH) receptors and neurotensin (NT) receptor-1 in stress-induced skin mast cell activation and increased vascular permeability, using both a mouse model and human skin biopsies. Restraint stress increases skin mast cell degranulation, CRH content and vascular permeability; these effects are unaffected in SP-/- and CRH-/- mice, but absent in W7WV mast cell deficient mice. CRH increases vascular permeability when injected intradermally in mice, but this effect is blocked by the NTR-1 antagonist SR48692 and is absent in NT -/- mice, demonstrating the critical role of NT. Stress may elicit release of CRH and NT from dorsal root ganglia (DRG) skin terminals and activate mast cells expressing functional CRHR and NTR-1. The clinical relevance of these findings is evidenced by increased expression of CRHR-1 and histidine decarboxylase (HOC) in affected skin from patients with chronic urticaria, indicating the involvement of CRH and mast cells. The central hypothesis is that CRH released in the skin by acute stress, alone or together with NT, activates mast cells leading to increased vascular permeability and neurogenic inflammation. Guided by strong preliminary data, this hypothesis will be tested by pursuing four specific aims: (1) Determine the importance of CRHR and NTR-1 on stress and intradermal CRH-induced skin mast cell activation and vascular permeability using CRHR-1-/-, CRHR-2-/-, double CRHR -/-, or NTR-1-/- mice. (2) Determine if CRHR or NTR-1 need to be expressed on skin mast cells by reconstituting W/WV mast cell deficient mice with bone marrow progenitors from the appropriate CRHR-/- or NTR-1 -/- mice. (3) Investigate the expression of CRHR and NTR-1 in human skin biopsies from atopic dermatitis, chronic urticaria and psoriasis patients, and correlate findings with serum CRH levels and extent of stress by using the State-Trait Anxiety Inventory (STAI). (4) Investigate the effect of CRH and NT on release from human skin biopsy explants and human cultured mast cells of proinflammatory cytokines. Our approach is innovative because it utilizes knockout mice and reconstitution techniques to understand how stress-derived neuropeptides contribute to skin inflammation, and employs novel methods of assaying mediator release. The proposed research is significant because it is expected to advance understanding of how acute stress increases skin vascular permeability and neurogenic inflammation. This is an important and under investigated area of skin pathophysiology that has potential applicability to understanding the pathogenesis of skin diseases and screening compounds that may develop into novel and effective treatments.

描述（由申请人提供）：对于为什么压力会加重慢性荨麻疹和牛皮癣等皮肤病，我们的理解存在根本性差距。这项研究的长期目标是确定肥大细胞在炎症性疾病中的作用。本应用的目的是使用小鼠模型和人类皮肤活检来确定促肾上腺皮质激素释放激素 (CRH) 受体和神经降压素 (NT) 受体 1 在应激诱导的皮肤肥大细胞激活和血管通透性增加中的作用。束缚应激会增加皮肤肥大细胞脱颗粒、CRH含量和血管通透性；这些作用在 SP-/- 和 CRH-/- 小鼠中不受影响，但在 W7WV 肥大细胞缺陷小鼠中不存在。当在小鼠皮内注射时，CRH 会增加血管通透性，但这种作用被 NTR-1 拮抗剂 SR48692 阻断，并且在 NT -/- 小鼠中不存在，这证明了 NT 的关键作用。压力可能会引起背根神经节 (DRG) 皮肤末端释放 CRH 和 NT，并激活表达功能性 CRHR 和 NTR-1 的肥大细胞。慢性荨麻疹患者受影响皮肤中 CRHR-1 和组氨酸脱羧酶 (HOC) 表达增加证明了这些发现的临床相关性，表明 CRH 和肥大细胞的参与。核心假设是，急性应激时皮肤中释放的 CRH（单独或与 NT 一起）会激活肥大细胞，导致血管通透性增加和神经源性炎症。在强有力的初步数据的指导下，该假设将通过追求四个具体目标进行检验：（1）使用CRHR-1-/-、CRHR-2-/-、双CRHR-/-或NTR-1-/-小鼠确定CRHR和NTR-1对应激和皮内CRH诱导的皮肤肥大细胞活化和血管通透性的重要性。 (2) 通过用适当的 CRHR-/- 或 NTR-1 -/- 小鼠的骨髓祖细胞重建 W/WV 肥大细胞缺陷型小鼠，确定 CRHR 或 NTR-1 是否需要在皮肤肥大细胞上表达。 (3) 研究特应性皮炎、慢性荨麻疹和银屑病患者皮肤活检中 CRHR 和 NTR-1 的表达，并使用状态-特质焦虑量表 (STAI) 将结果与血清 CRH 水平和应激程度相关联。 (4)研究CRH和NT对人皮肤活检外植体和人培养肥大细胞释放促炎细胞因子的影响。我们的方法是创新的，因为它利用基因敲除小鼠和重构技术来了解应激源性神经肽如何导致皮肤炎症，并采用测定介质释放的新方法。这项研究意义重大，因为它有望促进人们对急性应激如何增加皮肤血管通透性和神经源性炎症的理解。这是皮肤病理生理学的一个重要且正在研究的领域，它对于了解皮肤疾病的发病机制和筛选可能发展成新型有效治疗方法的化合物具有潜在的适用性。