Title: Role of microRNA molecules in therapeutic response to leukotriene modifying agents in asthma. The Principal Investigator, Dr. Amber Dahlin, Ph.D., MMSc., is committed to becoming an independent investigator focusing on highly innovative, translational, patient-oriented research in asthma. Her long-term goal is to identify, develop and implement new knowledge and methods to improve therapeutic outcomes for reducing the burden of asthma worldwide. The goal of this project is to identify the microRNAs (miRNAs) and their target genes that contribute to leukotriene modifier response in asthmatics. Although miRNAs are known to affect immune response pathways related to asthma, few studies to date have examined the role of these molecules on asthma development, progression and management. miRNAs are yet to be directly implicated in the clinical response to leukotriene modifiers, or in asthma subtypes including aspirin associated respiratory disease (AERD), which is characterized by excessive production of leukotrienes. In this revised application, Dr. Dahlin proposes to identify miRNAs, and their targets, associated with pharmacological and clinical response to montelukast in a cellular model of leukotriene perturbation using immortalized B cells from asthmatic patients, in addition to sera and primary B cells from a case-controlled AERD patient cohort, and then integrate the these data using bioinformatic approaches to construct predictive network models of montelukast response. Understanding the role of miRNA networks will enhance the pursuit of effective therapeutic outcomes in asthma treatment and provides a unique opportunity to reduce public health burden. Working closely with her mentor, Dr. Scott Weiss at Harvard Medical School, while completing these studies, she will also build her skills as a PI in personalized medicine through taking relevant coursework, attending meetings and conferences, and meeting with her collaborative clinical research team. Her committed mentors and collaborators will support her submission of an R01 grant proposal in the final years of this award period. In September 2014, Dr. Dahlin was promoted to the faculty rank of Instructor in Medicine at Harvard Medical School, demonstrating the institution?s commitment to her career development. This NHLBI Mentored Research Scientist Development Award (K01) will allow Dr. Dahlin to merge a translational epidemiological approach with network modeling to investigate the relationship between miRNA networks and treatment response in asthma, with the goal of improving therapeutic outcomes for asthma patients.

Public Health Relevance

This study proposes a novel investigation of the relationship between miRNAs and treatment response to leukotriene modifying agents, with the ultimate goal of improving therapeutic outcomes in asthma patients. Understanding which patients are likely to benefit from a particular asthma medication will improve patient care and guide physicians in selecting appropriate treatment regimens for their patients, while developing new insights into molecular pathways involved in leukotriene modifier response is expected to aid in development of more effective therapies for asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HL130629-02
Application #
9316699
Study Section
Special Emphasis Panel (MCBS (MA))
Program Officer
Tigno, Xenia
Project Start
2016-07-15
Project End
2021-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
$178,200
Indirect Cost
$13,200
Name
Brigham and Women's Hospital
Department
Type
Independent Hospitals
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Panganiban, Ronald A; Sun, Maoyun; Dahlin, Amber et al. (2018) A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis. J Allergy Clin Immunol 142:1469-1478.e2
Mak, Angel C Y; White, Marquitta J; Eckalbar, Walter L et al. (2018) Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma. Am J Respir Crit Care Med 197:1552-1564
Dahlin, Amber; Qiu, Weiliang; Litonjua, Augusto A et al. (2018) The phosphatidylinositide 3-kinase (PI3K) signaling pathway is a determinant of zileuton response in adults with asthma. Pharmacogenomics J 18:665-677
McGeachie, Michael J; Davis, Joshua S; Kho, Alvin T et al. (2017) Asthma remission: Predicting future airways responsiveness using an miRNA network. J Allergy Clin Immunol 140:598-600.e8
Lasky-Su, Jessica; Dahlin, Amber; Litonjua, Augusto A et al. (2017) Metabolome alterations in severe critical illness and vitamin D status. Crit Care 21:193
Kelly, Rachel S; Dahlin, Amber; McGeachie, Michael J et al. (2017) Asthma Metabolomics and the Potential for Integrative Omics in Research and the Clinic. Chest 151:262-277
Kelly, Rachel S; Croteau-Chonka, Damien C; Dahlin, Amber et al. (2017) Integration of metabolomic and transcriptomic networks in pregnant women reveals biological pathways and predictive signatures associated with preeclampsia. Metabolomics 13:
Jiang, Xiaofeng; Dahlin, Amber; Weiss, Scott T et al. (2017) A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor. Sci Rep 7:7405
Dahlin, Amber; Weiss, Scott T (2016) Genetic and Epigenetic Components of Aspirin-Exacerbated Respiratory Disease. Immunol Allergy Clin North Am 36:765-789