New innovations: advancing mast cell biology

新创新：推进肥大细胞生物学

基本信息

批准号：
10508026
负责人：
Mark Christopher Siracusa
金额：
$ 23.55万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-23 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10508026
关键词：
Address Affect Allergic inflammation Anaphylaxis Antihistamines Carbonic Anhydrase Inhibitors Cell Line Cell physiology Cells Cellular Immunity Cellular biology Clinical Connective Tissue Data Development Diphtheria Toxin Disease Enterobacteria phage P1 Cre recombinase Enzyme Inhibitor Drugs Enzymes Family member German population Helminths Histamine Production Histamine Release Human Immune In Vitro Infection Inflammation Inflammation Mediators Knowledge Leukotrienes Life LoxP-flanked allele Lung Mast Cell Stabilizer Mediating Metabolic acidosis Modeling Monitor Mucous Membrane Mus Muscle Contraction Parasites Pathology Pathway interactions Patients Pharmacology Population Prostaglandins Pruritus Publishing Reaction Scientist Skin Smooth Muscle Stimulus Surface Symptoms Syndrome Tamoxifen Terminator Codon Testing Tetradecanoylphorbol Acetate Therapeutic Time Trichinella spiralis Work carbonate dehydratase common symptom defined contribution design diphtheria toxin receptor experimental study in vivo innovation mast cell mastocytosis mouse model new therapeutic target novel novel therapeutics pathogen prevent progenitor promoter response stem cells tool treatment strategy

项目摘要

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.

摘要：肥大细胞是疾病的主要驱动因素，包括肥大细胞增多症，肥大细胞激活综合征（MCAS），过敏性炎症和致命的过敏反应。一旦激活，肥大细胞促进通过强大的组胺，白细胞，前列腺素和许多其他许多其他组合产生的炎症促进瘙痒，燃烧，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是规定的抗组胺药和肥大细胞稳定剂，治疗选择有限，并且严重形式疾病仍然威胁生命。此外，对调节桅杆的因素的不完全理解细胞开发极大地限制了设计新型治疗剂的能力，以选择性地靶向肥大细胞。我们最近的研究表明，酶碳酸酐酶（CAR）1仅是由肥大细胞祖细胞表达。此外，我们已经证明了CAR1的药理抑制足以预防鼠和人类肥大细胞的发育。此外，我们的数据证明了体内用碳酸酐酶抑制剂治疗足以防止肥大细胞的发育和炎症鼠类感染，过敏性炎症和肥大性的鼠模型。总的来说，这些研究将CAR1确定为肥大细胞发育的关键调节剂和用于治疗肥大细胞的新型治疗靶点介导的炎症。尽管有这些重大进展，但肥大细胞是否仅由CAR1-产生在基线和炎症的背景下表达祖细胞尚待定义。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，我们已经生成了一种新型的小鼠模型，该模型在控制的 CAR1启动子。我们将使用这个新开发的鼠标模型来回答以下重要问题：目标1 将执行命运映射实验，以系统地评估表达CAR1的贡献肥大细胞的种群扩展的祖细胞响应各种刺激。 AIM 2将执行血统 - 特定的缺失实验以靶向表达CAR1的祖细胞并测试其对各种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型的鼠标模型，该模型第一次可以专门删除肥大细胞祖细胞。考虑到我们的大量知识差距了解肥大细胞开发，该新工具有潜力促进重大进展肥大细胞生物学。