New innovations: advancing mast cell biology

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因素 （MCAS），过敏性炎症和致命的过敏反应。肥大细胞一旦被激活， 炎症通过他们强大的生产组胺，白三烯，白藜芦醇和许多其他 促进瘙痒、烧灼感、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。虽然患有这些症状的患者 处方的抗组胺药和肥大细胞稳定剂，治疗选择有限，严重的形式，这些 疾病仍然威胁生命。此外，对调节肥大细胞的因素的不完全理解， 细胞的发展极大地限制了设计新的治疗方法的能力， 肥大细胞我们最近的研究表明，碳酸酐酶（Car）1是唯一的 由肥大细胞祖细胞表达。此外，我们已经证明了对Car 1的药理学抑制是 足以防止鼠和人肥大细胞发育。此外，我们的数据表明，在体内， 用碳酸酐酶抑制剂治疗足以防止肥大细胞发育和炎症， 感染、过敏性炎症和肥大细胞增多症的鼠模型。总的来说，这些研究将Car 1确定为 肥大细胞发育的关键调节剂和肥大细胞治疗的新治疗靶点- 介导的炎症。尽管有这些重要的进展，肥大细胞是否只产生于Car 1- 在基线和在炎症情况下表达祖细胞仍有待确定。此夕h 特异性靶向表达Car 1的祖细胞的治疗潜力是未知的。为了解决这个问题，我们 已经产生了一种新的小鼠模型，其中三苯氧胺（TAM）诱导的Cre重组酶在 Car 1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： 将进行命运定位实验，以系统地评估Car 1表达的贡献。 肥大细胞的群体扩增响应于不同的刺激。目标2将执行血统- 特异性缺失实验，靶向表达Car 1的祖细胞，并测试它们对不同形式 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，可以特异性地删除肥大细胞祖细胞。鉴于我们在知识上的巨大差距， 了解肥大细胞的发展，这种新的工具有可能促进重大进展， 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.