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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：
10112819
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/10112819
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/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.

项目概要/摘要该提案描述了一项为期 5 年的培训奖励，以发展校长的学术生涯研究员 Melanie C. Dispenza，医学博士、哲学博士，西北大学委员会认证的过敏症免疫学家大学范伯格医学院。她的资历和背景，结合她目前的研究防止 IgE 介导的肥大细胞和嗜碱性粒细胞的激活，使她具有独特的资格来研究新的预防过敏反应的疗法。在本提案期间，迪斯彭萨博士将至少继续投入 75% 的努力致力于以患者为导向的转化研究。过敏反应是一种可能危及生命的 IgE 介导的全身过敏反应，目前尚不清楚预防性治疗。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有意接触引起的过敏反应，后者包括脱敏和免疫疗法。布鲁顿酪氨酸激酶 (BTK) 是人类肥大细胞中 FcεRI 信号传导的关键组成部分和嗜碱性粒细胞。 BTK的药理学抑制剂一般耐受性良好，初步数据显示BTK 抑制剂在体外和小鼠模型中有效阻断 IgE 介导的人类肥大细胞和嗜碱性粒细胞活化体内过敏反应。因此，利用 BTK 抑制剂来主动预防过敏反应是可能的。包括过敏反应。该提案的总体假设是短期使用 FDA 批准的 BTK 依鲁替尼等抑制剂可以预防两种过敏反应小鼠模型中药物引起的过敏反应和人类。如果成功的话，BTK 抑制剂可能会被用来使药物脱敏变得更安全、更安全。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，迪彭萨博士将努力实现她成为一名独立转化医师科学家。短期目标包括（1）扩大肥大细胞研究技能生物学，(2) 学习实施新型人源化小鼠过敏反应模型，以及 (3) 获取生物统计数据以及研究设计和实施的临床试验技能。获得该奖项后，迪斯彭萨博士将接受过必要的培训，以设计和实施有关制定新战略的进一步研究预防过敏反应。为了实现这些目标，我们组建了一支优秀的指导团队。初级导师布鲁斯·博赫纳 (Bruce Bochner) 医学博士（医学系过敏免疫学部教授）拥有强大的过敏症转化研究（包括肥大细胞生物学）的跟踪记录，并成功培训了许多院士们。 Donald MacGlashan，Jr，医学博士，哲学博士（约翰斯医学院过敏和临床免疫学部主任霍普金斯大学）将担任联合导师，在肥大细胞和嗜碱性粒细胞激活和发信号。指导团队将监督迪斯彭萨博士在发展必要技能方面的进展，以便支持她转型为独立调查员。