New innovations: advancing mast cell biology

摘要：肥大细胞是肥大细胞增多症、肥大细胞活化综合征等疾病的主要驱动力。 (MCAS)，过敏性炎症和致命的过敏反应。一旦激活，肥大细胞就会促进 通过大量产生组胺、白三烯、前列腺素和许多其他物质引起的炎症 促进瘙痒、灼热、平滑肌收缩和过敏反应的效应分子；所有这些都是 肥大细胞介导的炎症的常见症状。尽管患有这些症状的患者 处方的抗组胺药物和肥大细胞稳定剂，治疗选择有限，以及这些的严重形式 疾病仍然威胁着生命。此外，对调节桅杆的因素的理解也不全面。 细胞发展极大地限制了设计有选择性靶向的新型疗法的能力 肥大细胞。我们最近的研究表明，碳酸氢酶(CAR)1是唯一的 由肥大细胞前体细胞表达。此外，我们还证明了Car1的药理抑制是 足以阻止小鼠和人类肥大细胞的发育。此外，我们的数据表明，在活体内 碳酸酐酶抑制剂的治疗足以防止肥大细胞的发育和炎症 感染、过敏性炎症和肥大细胞增多症的小鼠模型。总而言之，这些研究确定CA1是 肥大细胞发育的关键调节因子和肥大细胞治疗的新靶点- 介导性炎症。尽管有这些重大进展，无论肥大细胞是否完全起源于Car1- 在基线和炎症的背景下，祖细胞的表达仍有待确定。此外， 特异性靶向表达Car1的祖细胞的治疗潜力尚不清楚。为了解决这个问题，我们 已经建立了一种新的小鼠模型，该模型具有三苯氧胺()可诱导的Cre重组酶，并受 Car1启动子。我们将使用这个新开发的小鼠模型来回答这些重要的问题：目标1 将进行命运映射实验，系统地评估Car1表达的贡献 肥大细胞在不同刺激下群体扩张的祖细胞。目标2将执行世系- 针对表达Car1的祖细胞的特异性缺失实验并测试它们对不同形式的贡献 肥大细胞介导的炎症。这些重要的研究将有助于验证一种新的小鼠模型， 第一次，可以专门删除肥大细胞祖细胞。鉴于我们在知识方面的巨大差距 了解肥大细胞的发育，这一新工具有可能促进在 肥大细胞生物学。

Summary: Mast cells are the main drivers of diseases including mastocytosis, mast cell activation syndrome (MCAS), allergic inflammation and deadly anaphylaxis reactions. Once activated, mast cells promote inflammation through their robust production of histamines, leukotrienes, prostaglandins and many other effector molecules that promote itching, burning, smooth muscle contraction and anaphylaxis; all of which are common symptoms of mast cell-mediated inflammation. Although patients suffering from these symptoms are prescribed antihistamines and mast cell stabilizers, treatment options are limited, and severe forms of these diseases remain life-threatening. Further, an incomplete understanding of the factors that regulate mast cell development has dramatically limited the ability to design novel therapeutics that selectively target mast cells. Our recent studies have revealed that the enzyme carbonic anhydrase (Car)1 is exclusively expressed by mast cell progenitors. Further, we have demonstrated that pharmacologic inhibition of Car1 is sufficient to prevent murine and human mast cell development. Moreover, our data demonstrate that in vivo treatment with carbonic anhydrase inhibitors is sufficient to prevent mast cell development and inflammation in murine models of infection, allergic inflammation and mastocytosis. Collectively, these studies identify Car1 as a critical regulator of mast cell development and a novel therapeutic target for the treatment of mast cell- mediated inflammation. Despite these significant advances, whether mast cells exclusively arise from Car1- expressing progenitors at baseline and in the context of inflammation remains to be defined. Further, the therapeutic potential of specifically targeting Car1-expressing progenitors is unknown. To address this, we have generated a novel mouse model with a tamoxifen (TAM) inducible Cre recombinase under control of the Car1 promoter. We will use this newly developed mouse model to answer these important questions: Aim 1 will perform fate mapping experiments to systematically evaluate the contributions of Car1-expressing progenitors to the population expansion of mast cells in response to diverse stimuli. Aim 2 will perform lineage- specific deletion experiments to target Car1-expressing progenitors and test their contributions to diverse forms of mast cell-mediated inflammation. These important studies will help to validate a novel mouse model that, for the first time, can specifically delete mast cell progenitors. Given the substantial knowledge gaps in our understanding of mast cell development, this new tool has the potential to promote significant advances in mast cell biology.