Itch, proteases and protease-activated receptors

瘙痒、蛋白酶和蛋白酶激活受体

• 批准号: 8115068
• 负责人: Ethan A Lerner
• 金额: $ 37.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115068
• 关键词: 3-Dimensional; Abbreviations; Address; Antigen Presentation; Arthritis; Asthma; Atherosclerosis; Atopic Dermatitis; Binding Sites; Biochemical; Bone Resorption; Cathepsins; Cicatrix; Clinical; Cutaneous; Cysteine Protease; Data; Dermatologic; Development; Distress; Dorsal; Elastin; Epidermis; Esthesia; Felis catus; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; Ganglia; Goals; Histamine; Histamine Release; Homologous Gene; Human; Immunohistochemistry; Inflammation; Inflammatory; Interferons; Interleukins; Investigation; Janus kinase; Knockout Mice; Lead; Ligands; Link; Mediating; Mediator of activation protein; Mucuna; Nature; Nociception; Osteitis; PAR-2 Receptor; PAWR gene; Pathway interactions; Peptide Hydrolases; Peripheral; Pharmaceutical Preparations; Plants; Process; Promoter Regions; Proteinase-Activated Receptors; Proteins; Proteolytic Processing; Pruritus; Role; Route; STAT protein; Serine Protease; Signal Transduction; Signaling Molecule; Skin; Stimulus; Symptoms; T-Cell Lymphoma; Testing; Urticaria; cathepsin K; cytokine; design; improved; inhibitor/antagonist; keratinocyte; novel; public health relevance; receptor; receptor function; research study; secondary infection; sensor; skin disorder

DESCRIPTION (provided by applicant): Pruritus is a major symptom of dermatologic and internal conditions. It can be difficult to treat, as few specific inhibitors of itch are available and the mechanism that triggers the sensation of itch is not clear. Although most experimental studies of itch use histamine as the pruritic stimulus, most cases of clinical pruritus are considered to be histamine independent. The discovery of natural compounds that evoke itch without releasing histamine might facilitate the search for endogenous mediators and receptors distinct from histamine. Spicules of the plant Mucuna pruriens (cowhage) when lodged in the epidermis produce moderate to severe itching that is independent of histamine. We have determined that the active compound in cowhage is mucunain, a cysteine protease. We have also determined that mucunain is a ligand for human protease-activated receptors 2 and 4. We hypothesized that human cysteine proteases might share homology with mucunain, activate these same receptors, and function as endogenous mediators of pruritus. We provide data that this is the case with certain cathepsins, notably Cathepsin S. Cathepsins have been implicated in many processes but have not previously been considered signaling molecules. The experiments proposed in Aim 1 are designed to decipher the mechanism by which cysteine proteases activate their cognate receptors. Experiments proposed in Aim 2 with receptor knockout mice will determine if such receptors are indeed necessary for the nociceptive effects of cathepsin S. The promoter region of cathepsin S contains STAT binding sites leading us to hypothesize that the critical pruritus-associated cytokine IL-31 activates its receptor leading to the induction of cathepsin S expression. This hypothesis will be tested in Aim 3. The hypotheses and experiments presented here link together three molecules that have previously been associated independently with itch and inflammation: PARs, cathepsins and IL-31. PUBLIC HEALTH RELEVANCE: Itching is a major symptom of dermatologic and many internal conditions and is difficult to treat. The goal of this project is to examine how certain proteins, called cysteine proteases, not previously associated with itching, appear to turn on specific receptors and cause itching. The results of this project may lead to the development of new drugs to treat itch.

描述（由申请人提供）：瘙痒是皮肤病和内部疾病的主要症状。它可能很难治疗，因为很少有特异性的瘙痒抑制剂可用，并且触发瘙痒感觉的机制尚不清楚。虽然大多数瘙痒的实验研究使用组胺作为瘙痒刺激，但大多数临床瘙痒病例被认为是组胺非依赖性的。天然化合物引起瘙痒而不释放组胺的发现可能有助于寻找不同于组胺的内源性介质和受体。植物油麻藤的针状物（牛毛）当卡在表皮时，产生中度至重度瘙痒，这与组胺无关。我们已经确定，活性化合物的牛是粘蛋白酶，半胱氨酸蛋白酶。我们还确定了粘蛋白酶是人蛋白酶激活受体2和4的配体。我们假设人类半胱氨酸蛋白酶可能与粘蛋白酶具有同源性，激活这些相同的受体，并作为瘙痒的内源性介质发挥作用。我们提供的数据表明，这是某些组织蛋白酶的情况，特别是组织蛋白酶S。组织蛋白酶参与许多过程，但以前没有被认为是信号分子。目的1中提出的实验旨在破译半胱氨酸蛋白酶激活其同源受体的机制。在目标2中提出的用受体敲除小鼠进行的实验将确定这些受体是否确实是组织蛋白酶S的伤害感受效应所必需的。组织蛋白酶S的启动子区含有STAT结合位点，这使我们假设关键的结肠炎相关细胞因子IL-31激活其受体，从而诱导组织蛋白酶S的表达。目标3将检验这一假设。这里提出的假设和实验将先前与瘙痒和炎症独立相关的三种分子联系在一起：PAR，组织蛋白酶和IL-31。 公共卫生相关性：瘙痒是皮肤病和许多内部疾病的主要症状，并且难以治疗。本项目的目标是研究某些蛋白质，称为半胱氨酸蛋白酶，以前与瘙痒无关，如何打开特定受体并引起瘙痒。该项目的结果可能会导致治疗瘙痒的新药的开发。