Regulation of CD23 Cleavage

CD23 裂解的调节

• 批准号: 7916894
• 负责人: Caroline Jeannette Padro
• 金额: $ 3.39万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916894
• 关键词: Affect; Agonist; Allergens; American; B-Lymphocytes; Binding; Bronchioles; Bronchoconstriction; Cells; Cleaved cell; Data; Disintegrins; Drug Delivery Systems; Enzymes; Exposure to; Extrinsic asthma; Family; Genetic Transcription; IgE; Laboratories; Ligands; Lung; Mediating; Membrane; Metalloproteases; Neurotransmitters; Norepinephrine; Pharmaceutical Preparations; Production; Regulation; Reporting; Severities; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Symptoms; Testing; Translating; beta-2 Adrenergic Receptors; novel; prevent; public health relevance; research study; response

DESCRIPTION (provided by applicant): IgE-mediated allergic asthma affects 10 million Americans. An allergic asthma attack is triggered by exposure to allergens that cause bronchoconstriction, which is relieved by the administration of a beta-2-adrenergic receptor ((2AR) agonist to relax smooth muscle cells surrounding the bronchioles. Other cells in the lung express the (2AR, including B lymphocytes that produce IgE. High levels of IgE translate into more severe allergic asthma symptoms. Our laboratory has reported that (2AR stimulation on an activated B cell increases the rate of IgE transcription. The natural ligand for the (2AR is the neurotransmitter norepinephrine, which is also associated with the severity of allergic asthma attacks. If the level of IgE is associated with the severity of an asthmatic response and if (2AR stimulation on a B cell increases IgE, it will be important to identify the mechanism that mediates this increase. IgE levels are regulated by the cleavage of membrane CD23 (mCD23) to soluble CD23 (sCD23), which, respectively, regulate IgE production negatively or positively. Our laboratory determined that there was a (2AR-induced increase in total cytoplasmic CD23 and sCD23, while mCD23 remained constant, suggesting that the mechanism involved in the regulation of mCD23 cleavage may be targeted by signaling intermediates activated after (2AR stimulation on a B cell. The enzymes that cleave mCD23 to sCD23 belong to a family of A Disintegrin And Metalloproteinases (ADAMs), which, when active, function to increase the positive soluble regulator of IgE, while keeping the negative membrane regulator constant. Although ADAM10 is reported to be the primary sheddase, our preliminary data show that the levels of ADAMs 8,10, and 28 increase in a B cell after activation, but that only the levels of ADAMs 8 and 28 increase further after concomitant (2AR stimulation. In experiments outlined in this proposal, we will test the hypothesis that (2AR stimulation on a B cell increases the ratio of sCD23/mCD23 and the subsequent level of IgE produced by regulating either the level and/or proteolytic activity of specific ADAMs. The significance of testing this hypothesis is that the data will elucidate a mechanism by which (2AR stimulation on a B cell participates in regulating the level of IgE, thus identifying novel drug targets in a B cell that would prevent agonist activity to overproduce IgE, without interfering with agonist activity on other cells that would relieve allergic asthma symptoms. PUBLIC HEALTH RELEVANCE: The current treatment for allergic asthma symptoms is to administer a beta-2 adrenergic receptor ((2AR) agonist drug, which binds to the (2AR expressed on bronchiole smooth muscle cells to cause them to relax, thus relieving bronchoconstriction. However, these agonists stimulate the (2AR on other cells, such as B cells to increase the level of IgE produced. Because the level of IgE is associated with the severity of allergic asthma symptoms, it will be important to identify the mechanism by which the 2(AR on a B cell increases IgE and if this mechanism is different from that used to relax bronchiole smooth muscle.

描述（由申请人提供）：IgE介导的过敏性哮喘影响1000万美国人。过敏性哮喘发作是由暴露于引起支气管收缩的过敏原引发的，通过给予β-2-肾上腺素能受体（2AR）激动剂以松弛细支气管周围的平滑肌细胞来缓解支气管收缩。肺中的其它细胞表达β 2 AR，包括产生IgE的B淋巴细胞。高水平的IgE会转化为更严重的过敏性哮喘症状。我们的实验室已经报道，对活化的B细胞的β 2 AR刺激增加IgE转录的速率。β 2 AR的天然配体是神经递质去甲肾上腺素，它也与过敏性哮喘发作的严重程度有关。如果IgE水平与哮喘反应的严重程度相关，并且如果对B细胞的β 2 AR刺激增加IgE，则鉴定介导这种增加的机制将是重要的。IgE水平由膜CD 23（mCD 23）裂解为可溶性CD 23（sCD 23）调节，可溶性CD 23分别负或正调节IgE产生。我们的实验室确定了β 2 AR诱导的总细胞质CD 23和sCD 23增加，而mCD 23保持不变，这表明参与调节mCD 23裂解的机制可能是通过在B细胞上β 2 AR刺激后激活的信号中间体来靶向的。将mCD 23裂解为sCD 23的酶属于A去整合素和金属蛋白酶（亚当斯）家族，其在活化时起作用以增加IgE的正可溶性调节物，同时保持负膜调节物恒定。虽然据报道ADAM 10是主要的脱落酶，但我们的初步数据显示，在B细胞活化后，亚当斯8、10和28的水平增加，但只有亚当斯8和28的水平在伴随β 2 AR刺激后进一步增加。在本建议中概述的实验中，我们将检验以下假设：对B细胞的β 2 AR刺激增加sCD 23/mCD 23的比率以及随后通过调节特定亚当斯的水平和/或蛋白水解活性产生的IgE水平。检验这一假设的意义在于，这些数据将阐明一种机制，通过该机制，对B细胞的β 2 AR刺激参与调节IgE水平，从而鉴定出B细胞中的新药物靶点，该靶点将阻止激动剂活性过度产生IgE，而不干扰对其他细胞的激动剂活性，从而缓解过敏性哮喘症状。 公共卫生相关性：目前治疗过敏性哮喘症状的方法是给予β-2肾上腺素能受体（2AR）激动剂药物，该药物与细支气管平滑肌细胞上表达的β 2AR结合，使其松弛，从而缓解支气管收缩。然而，这些激动剂刺激其它细胞如B细胞上的β 2 AR以增加产生的IgE水平。由于IgE水平与过敏性哮喘症状的严重程度相关，因此，重要的是要确定B细胞上的2 β AR增加IgE的机制，以及该机制是否不同于用于舒张细支气管平滑肌的机制。