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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：
10329987
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/10329987
关键词：
Agammaglobulinaemia tyrosine kinase Allergen Immunotherapy Allergens Allergic Allergic Reaction Anaphylaxis Award B-Cell Antigen Receptor 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 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 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.

项目总结/摘要本建议书描述了一个为期5年的培训奖励，以发展校长的学术生涯调查员梅兰妮·C Dispenza，医学博士，博士，西北大学董事会认证的过敏症免疫学家范伯格大学医学院。她的资历和背景，结合她目前的研究在阻止IgE介导的肥大细胞和嗜碱性粒细胞活化方面，使她成为唯一有资格研究新型预防过敏反应的治疗方法。在此期间，Dispenza博士将继续致力于至少 75%致力于以患者为导向的转化研究。过敏反应是一种潜在的危及生命的IgE介导的全身过敏反应，预防性治疗。对于可以降低频率和/或严重程度的疗法存在巨大的未满足需求意外和故意暴露引起的过敏反应，后者包括脱敏和免疫疗法。布鲁顿酪氨酸激酶（BTK）是人肥大细胞FcεRI信号转导的关键组分和嗜碱性粒细胞。BTK的药理学抑制剂通常耐受良好，初步数据显示BTK 抑制剂在体外和小鼠模型中有效阻断IgE介导的人肥大细胞和嗜碱性粒细胞活化体内过敏反应。因此，可能利用BTK抑制剂来主动预防过敏反应包括过敏反应该提案的总体假设是，短期使用FDA批准的BTK 在两种过敏反应小鼠模型中，在人类中也是如此。如果成功的话，BTK抑制剂有可能用于使药物脱敏更安全，成本效益更高，从而改善患者护理和结果。通过这项拟议中的研究，Dispenza博士将致力于她的长期目标，成为一个独立的翻译物理学家-科学家。短期目标包括：（1）扩大肥大细胞的研究技能生物学，（2）学习实施新的过敏反应的人源化小鼠模型，以及（3）获得生物统计学以及临床试验设计和实施技能。完成此奖项后，Dispenza博士将已经接受了设计和实施关于制定新战略的进一步研究的必要培训，预防过敏反应。为了实现这些目标，已经组建了一个优秀的指导团队。主导师，布鲁斯Bochner，医学博士（教授，过敏免疫学系，医学系），有很强的在包括肥大细胞生物学在内的变态反应转化研究方面的跟踪记录，并成功培训了许多院士们Donald MacGlashan，Jr，MD，PhD（过敏和临床免疫学部主任，Johns 霍普金斯大学），将担任共同导师，在肥大细胞和嗜碱性粒细胞活化，发信号。指导小组将监督Dispenza博士在发展必要技能方面的进展，支持她转型为独立调查员