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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/文摘