Using BTK Inhibitors to Prevent Anaphylactic Drug Reactions

使用 BTK 抑制剂预防过敏性药物反应

基本信息

批准号：
9890681
负责人：
Melanie C. Dispenza
金额：
$ 19.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-22 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9890681
关键词：
Agammaglobulinaemia tyrosine kinase Allergen Immunotherapy Allergens Allergic Allergic Reaction Anaphylaxis Award B-Lymphocytes Basophils Biological Markers Biometry CCL2 gene CD34 gene Cells Cellular biology Clinical Clinical Immunology Clinical Trials Cutaneous Data Development Doctor of Philosophy Dose Epinephrine Exposure to FDA approved Food Frequencies Funding Goals Grant Histamine Human Hypersensitivity Hypersensitivity skin testing IL8 gene IgE Immune response Immunologist Immunology Immunotherapy In Vitro Inflammatory Inpatients Insect Sting Interleukin-6 Kinetics Learning Leukocytes Leukotriene C4 Life Logic Measurement Mediating Mediator of activation protein Medicine Mentors Mus Nuts Oral Pathway interactions Patient Care Patients Penicillin Allergy Penicillins Peripheral Pharmaceutical Preparations Pharmacology Phase Phenotype Phosphotransferases Plasma Preventive therapy Principal Investigator Production Prostaglandin D2 Reaction Receptor Signaling Receptors, Antigen, B-Cell Research Research Design Research Personnel Risk Role Sampling Scientist Serum Severities Signal Pathway Signal Transduction Skin Small Interfering RNA Specificity Stimulus Study Skills TNF gene Testing Tissues Training Translational Research Trees Tryptase Tyrosine Kinase Inhibitor Universities Venoms Work X-Linked Agammaglobulinemia beta-n-acetylhexosaminidase care outcomes career cell type clinical care cost cost effective cytokine desensitization design experimental study food challenge human model human tissue humanized mouse improved in vivo in vivo Model inhibitor/antagonist mast cell medical schools mouse model novel novel strategies novel therapeutics open label patient oriented prevent professor skills skin prick test standard of care stem cells translational physician

项目摘要

PROJECT SUMMARY/ABSTRACT This proposal describes a 5-year training award to develop the academic career of the principal investigator, Melanie C. Dispenza, MD, PhD, a board-certified allergist-immunologist at the Northwestern University Feinberg School of Medicine. Her qualifications and background, combined with her current research in preventing IgE-mediated activation of mast cells and basophils, make her uniquely qualified to study novel therapies to prevent anaphylaxis. During the period of this proposal, Dr. Dispenza will continue to devote at least 75% effort towards patient-oriented translational research. Anaphylaxis is a potentially life-threatening IgE-mediated systemic allergic reaction with no known preventative therapies. There is a huge unmet need for therapies that can reduce the frequency and/or severity of anaphylactic reactions from both accidental and intentional exposures, the latter including desensitizations and immunotherapy. Bruton’s tyrosine kinase (BTK) is a key component of FcεRI signaling in human mast cells and basophils. Pharmacologic inhibitors of BTK are generally well tolerated, and preliminary data show that BTK inhibitors effectively block IgE-mediated human mast cell and basophil activation in vitro and in mouse models of anaphylaxis in vivo. Thus, it may be possible to utilize BTK inhibitors to proactively prevent allergic reactions including anaphylaxis. The overarching hypothesis of this proposal is that short-term use of FDA-approved BTK inhibitors such as ibrutinib will prevent medication-induced anaphylaxis in both mouse models of anaphylaxis and in humans. If successful, BTK inhibitors could potentially be used to make drug desensitization safer and more cost effective, thus improving patient care and outcomes. Through this proposed research, Dr. Dispenza will work towards her long-term goal of becoming an independent translational physician-scientist. Short-term goals include (1) expanding research skills in mast cell biology, (2) learning to implement novel humanized mouse models of anaphylaxis, and (3) acquiring biostatistical and clinical trial skills for study design and implementation. After completion of this award, Dr. Dispenza will have had the needed training to design and implement further studies on the development of novel strategies to prevent anaphylaxis. To achieve these goals, an excellent mentoring team has been assembled. The primary mentor, Bruce Bochner, MD (Professor, Division of Allergy-Immunology, Department of Medicine), has a strong track record of translational research in allergy including mast cell biology and has successfully trained many academicians. Donald MacGlashan, Jr, MD, PhD (Director, Division of Allergy and Clinical Immunology, Johns Hopkins University), will serve as co-mentor, with additional expertise in mast cell and basophil activation and signaling. The mentoring team will oversee Dr. Dispenza’s progress in developing the necessary skills in order to support her transition into an independent investigator.

项目摘要/摘要该提案描述了一项为期5年的培训奖，以发展校长的学术生涯调查员，梅兰妮·C·德克森扎（Melanie C. Dispenza），医学博士，博士，西北部的董事会认证过敏症主义者 - 免疫学家大学费恩伯格医学院。她的资格和背景以及她目前的研究在防止IgE介导的肥大细胞和嗜碱性粒细胞的激活时，使她具有独特的资格来研究新型预防过敏反应的疗法。在此提案期间，Dispenza博士至少将继续致力于 75％的努力致力于患者的转化研究。过敏反应是一种潜在威胁生命的IgE介导的全身过敏反应，尚无预防性疗法。对疗法的需求巨大，可以降低频率和/或严重性意外和故意暴露的过敏反应，后者包括脱敏和免疫疗法。 Bruton的酪氨酸激酶（BTK）是人类肥大细胞中FcεRI信号的关键组成部分和嗜碱性粒细胞。 BTK的药理抑制剂通常耐受性良好，初步数据表明BTK 抑制剂有效地阻断IgE介导的人类肥大细胞和嗜碱性粒细胞在体外和小鼠模型中的活化体内过敏反应。这是有可能利用BTK抑制剂主动防止过敏反应的包括过敏反应。该提案的总体假设是短期使用FDA批准的BTK 诸如ibrutinib之类的抑制剂将防止两种小鼠过敏反应中的药物诱导的过敏反应和人类。如果成功的话，可以使用BTK抑制剂使药物脱敏更安全，并且更具成本效益，从而改善患者护理和结果。通过这项拟议的研究，Dispenza博士将致力于成为一个长期目标独立翻译的物理科学家。短期目标包括（1）扩大肥大细胞中的研究技能生物学，（2）学习实施过敏反应的新型人性化小鼠模型，（3）获得生物统计学以及研究设计和实施的临床试验技能。完成此奖项后，Dispenza博士将已经进行了必要的培训，以设计和实施有关新型策略发展的进一步研究预防过敏反应。为了实现这些目标，已经组建了一支出色的心理团队。主要导师，医学博士Bruce Bochner（医学系过敏 - 免疫学教授）过敏研究的转化研究记录，包括肥大细胞生物学，并成功训练了许多院士。小唐纳德·麦格拉山（Donald MacGlashan）霍普金斯大学），将担任副委员信号。指导团队将监督Dispenza博士在开发必要技能方面的进步支持她过渡到独立调查员。