Using BTK Inhibitors to Prevent Anaphylactic Drug Reactions

项目摘要/摘要 这项建议描述了一项为期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，西北大学董事会认证的过敏症专科医生和免疫学家 费恩伯格大学医学院。她的资历和背景，结合她目前的研究 在防止IgE介导的肥大细胞和嗜碱性粒细胞激活方面，使她成为唯一有资格研究小说的人 预防过敏反应的疗法。在这项提议期间，Dispenza博士将继续致力于至少 75%的精力用于以患者为导向的翻译研究。 过敏反应是一种潜在威胁生命的IgE介导的全身性过敏反应，目前尚不清楚 预防性治疗。有一个巨大的未得到满足的治疗需求，可以降低频率和/或严重程度 意外暴露和故意暴露引起的过敏反应，后者包括脱敏 和免疫疗法。布鲁顿酪氨酸激酶是人肥大细胞FcεRI信号的关键成分 以及嗜碱性粒细胞。BTK的药物抑制剂一般耐受性良好，初步数据显示BTK 在体外和小鼠模型中，抑制剂有效地阻断IgE介导的人肥大细胞和嗜碱性粒细胞的激活 体内的过敏性反应。因此，利用btk抑制剂主动预防过敏反应是可能的。 包括过敏反应。这项提议的首要假设是，短期使用FDA批准的BTK 伊布鲁替尼等抑制剂可以预防两种过敏反应模型的药物引起的过敏反应。 在人类身上也是如此。如果成功，BTK抑制剂可能被用于使药物脱敏更安全和 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博士将努力实现她的长期目标，即成为 独立翻译医生兼科学家。短期目标包括(1)扩大肥大细胞的研究技能 生物学，(2)学习实现过敏反应的新的人性化小鼠模型，以及(3)获得生物统计学 以及研究设计和实施的临床试验技能。在完成这一奖项后，Dispenza博士将 接受了所需的培训，以设计和实施关于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，已经组建了一支优秀的指导团队。初级阶段 导师布鲁斯·博什内尔医学博士(医学系过敏免疫科教授) 有包括肥大细胞生物学在内的过敏症翻译研究的记录，并成功地培训了许多 院士们。Donald Macglashan，Jr，MD，PhD(Johns过敏和临床免疫学部主任 将担任共同导师，并拥有肥大细胞和嗜碱性粒细胞激活方面的额外专业知识 发信号。指导团队将监督Dispenza博士在培养必要技能方面的进展 以支持她转变为独立调查员。

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.