Membrane Serine Protease Activities in Protease Activated Receptor Signaling

蛋白酶激活受体信号转导中的膜丝氨酸蛋白酶活性

基本信息

批准号：
9181449
负责人：
Toni M Antalis
金额：
$ 38.38万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-23 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9181449
关键词：
Affect Agonist Animal Model Anthrax disease Anti-Inflammatory Agents Anti-inflammatory Arthritis Asthma Binding Biological Blood capillaries Calcium Signaling Cardiovascular Diseases Cell Culture Techniques Cell membrane Cell surface Cells Clinical Trials Colitis Data Dependence Development Disease Endothelial Cells Engineering Environment Enzyme Precursors Epithelial Epithelial Cells Family G-Protein-Coupled Receptors Goals Growth Health Homeostasis Host Defense Human In Vitro Individual Intestines Lead Maintenance Malignant Neoplasms Mediating Membrane Modeling Molecular Mus Nature Nerve Degeneration PRSS8 gene Pathway interactions Peptide Hydrolases Permeability Physiological Play Process Prodrugs Proteinase-Activated Receptors Receptor Signaling Research Role Serine Protease Signal Pathway Signal Transduction Signaling Molecule Surface System Testing Therapeutic Therapeutic Effect Therapeutic Uses Tissues Toxin Vascular Endothelium angiogenesis anthrax toxin base capillary cofactor experimental study extracellular improved in vivo intestinal epithelium killings matriptase molecular targeted therapies neoplastic cell novel novel therapeutic intervention ovarian neoplasm overexpression prevent public health relevance response sensor testisin therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Protease-activated receptors (PARs) are distinct G protein-coupled receptors (GPCRs) that allow cells to sense specific proteases in their environment. PARs are emerging as attractive therapeutic targets for several diseases, including cardiovascular diseases, arthritis, colitis, asthma, neurodegenerative conditions and cancer. Individual PARs are able to activate pathways that confer both barrier disruptive, proinflammatory signaling, as well as anti-inflammatory barrier protective signaling pathways. How this selective signaling is mediated is poorly understood, and represents a significant impediment to the development of effective agonists and antagonists targeting PARs for therapeutic uses. A better understanding of the nature of the protease environment that induces differential PAR signaling, and the molecular mechanisms involved in protease activation of PARs are critical. We have discovered that two membrane-anchored serine proteases, Testisin and Matriptase, are cell-specific endogenous activators of PAR2, and likely modulate localized spatial and temporal signaling of PAR2 in endothelial and epithelial cells, respectively. Our data suggests that the GPI anchored serine protease, Testisin, is a proangiogenic factor that can activate PAR2 in the microvasculature, and facilitate capillary growth important for angiogenesis. We also find that the transmembrane serine protease, Matriptase, may sustain a PAR2 dependent signaling pathway important for maintaining the intestinal epithelial barrier. The goal of the research plan is to define the activities of these PAR2-activating membrane serine proteases and to develop a novel prodrug strategy for both detecting and targeting their activities. The research plan will utilize in vitro cultures in concert with in vivo studies in mic to test the following aims: 1) to determine the contribution of Testisin to PAR2 signaling during angiogenesis, 2) to determine the role of PARs in regulating in regulating Prostasin->Matriptase mediated intestinal epithelial barrier closure, and 3) to reengineer anthrax toxins to target PAR2-activating membrane-anchored serine proteases on the cell surface.

描述（由申请人提供）：蛋白酶激活的受体（PAR）是不同的G蛋白偶联受体（GPCR），可让细胞在其环境中感知特定的蛋白酶。 Pars成为了多种疾病的有吸引力的治疗靶标，包括心血管疾病，关节炎，结肠炎，哮喘，神经退行性疾病和癌症。单个PAR能够激活赋予屏障破坏性，促炎信号传导以及抗炎屏障保护信号通路的途径。该选择性信号如何介导的理解很少，这代表了针对治疗用途的PAR的有效激动剂和拮抗剂的发展的重要障碍。更好地理解诱导差异PAR信号传导的蛋白酶环境的性质，以及参与PAR的蛋白酶激活的分子机制至关重要。我们已经发现，膜锚定的丝氨酸蛋白酶（睾丸蛋白和肌蛋白酶）是PAR2的细胞特异性内源性激活剂，可能分别调节pAR2的局部空间和时间信号传导，分别在内皮和上皮细胞中。我们的数据表明，GPI锚定的丝氨酸蛋白酶睾丸是一种可激活微脉管系统中PAR2的促血管生成因子，并促进毛细血管生长对于血管生成很重要。我们还发现，跨膜丝氨酸蛋白酶Matriptase可能维持PAR2依赖性信号传导途径对于维持肠上皮屏障很重要。研究计划的目的是定义这些PAR2激活膜丝氨酸蛋白酶的活动，并制定一种新颖的前药策略来检测和针对其活动。该研究计划将与MIC中的体内研究一起利用体外培养物来测试以下目的：1）确定睾丸对血管生成期间睾丸对PAR2信号的贡献，2）确定PAR在调节调节前列腺素> Matriptase介导的近视式屏障对靶向靶向2）中的作用，以及3）对3）介导的靶向2）细胞表面上的膜锚定丝氨酸蛋白酶。