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

• 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
• 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

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）：蛋白酶激活受体（PARs）是不同的G蛋白偶联受体（gpcr），允许细胞在其环境中感知特定的蛋白酶。PARs正在成为几种疾病的有吸引力的治疗靶点，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。个体PARs能够激活屏障破坏、促炎信号通路和抗炎屏障保护信号通路。这种选择性信号是如何介导的尚不清楚，这是开发针对PARs的有效激动剂和拮抗剂用于治疗的一个重大障碍。更好地了解诱导不同PAR信号的蛋白酶环境的性质以及PAR的蛋白酶激活的分子机制是至关重要的。我们已经发现两种膜锚定丝氨酸蛋白酶，睾丸蛋白酶和基质蛋白酶，是细胞特异性内源性PAR2激活剂，可能分别调节内皮细胞和上皮细胞中PAR2的局部空间和时间信号。我们的数据表明，GPI锚定的丝氨酸蛋白酶睾丸素是一种促血管生成因子，可以激活微血管中的PAR2，促进对血管生成至关重要的毛细血管生长。我们还发现跨膜丝氨酸蛋白酶（Matriptase）可能维持PAR2依赖性信号通路，这对维持肠上皮屏障很重要。研究计划的目标是确定这些par2激活膜丝氨酸蛋白酶的活性，并开发一种新的前药策略来检测和靶向它们的活性。该研究计划将利用体外培养和体内研究来测试以下目标：1)确定睾丸素在血管生成过程中对PAR2信号的贡献，2)确定PARs在调节Prostasin->基质酶介导的肠上皮屏障关闭中的作用，以及3)重组炭疽毒素以靶向细胞表面PAR2激活膜锚定丝氨酸蛋白酶。

项目成果

Coagulation signaling to epithelia.

向上皮细胞发出凝血信号。

• DOI: 10.1182/blood-2016-05-715052
• 发表时间: 2016
• 期刊: Blood
• 影响因子: 20.3
• 作者: Antalis,ToniM