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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：
10626157
负责人：
Mark Christopher Siracusa
金额：
$ 19.63万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10626157
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 Maps Mast Cell Stabilizer Mediating Meditation Metabolic acidosis Modeling Monitor Mucous Membrane Mus Muscle Contraction Parasites Pathology Pathway interactions Patients 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 inducible Cre innovation mast cell mastocytosis mouse model new therapeutic target novel novel therapeutics pathogen pharmacologic 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.

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