Itch, proteases and protease-activated receptors

瘙痒、蛋白酶和蛋白酶激活受体

• 批准号: 8501380
• 负责人: Ethan A Lerner
• 金额: $ 36.04万
• 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/8501380
• 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(申请人提供)：瘙痒是皮肤病和内科疾病的主要症状。这可能很难治疗，因为可用的止痒特效药很少，而且引发瘙痒感觉的机制尚不清楚。虽然大多数关于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。在不释放组胺的情况下引起瘙痒的天然化合物的发现，可能有助于寻找与组胺截然不同的内源性介质和受体。当植物绒毛(母牛)的针状物停留在表皮时，会产生中度到重度的瘙痒，这种瘙痒不依赖于组胺。我们已确定母牛饲料中的活性物质为粘蛋白，一种半胱氨酸蛋白酶。我们还确定粘蛋白是人蛋白水解酶激活受体2和4的配基。我们推测，人半胱氨酸蛋白酶可能与粘蛋白有同源性，激活这些受体，并作为内源性的瘙痒介质发挥作用。我们提供的数据表明，某些组织蛋白就是这种情况，特别是组织蛋白S。组织蛋白参与了许多过程，但以前并不被认为是信号分子。在目标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。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伤害性效应所必需的。组织蛋白S的启动子区域包含STAT结合部位，这使我们假设关键的瘙痒相关细胞因子IL-31激活其受体，从而诱导组织蛋白S的表达。这一假说将在《目标3》中得到验证。这里提出的假说和实验将三种以前被认为与瘙痒和炎症独立相关的分子联系在一起：PARS、组织蛋白和IL-31。 公共卫生相关性：瘙痒是皮肤病和许多内科疾病的主要症状，很难治疗。这个项目的目标是研究某些被称为半胱氨酸蛋白酶的蛋白质是如何启动特定的受体并导致瘙痒的，这些蛋白质以前与瘙痒无关。该项目的结果可能会导致治疗瘙痒的新药的开发。