This proposal describes a 5-year mentored training program to provide the candidate, Dr. Michele Kong, with intensive training in the areas of cellular and molecular mechanisms of inflammation, matrix destruction, protease antiprotease imbalance and pathogenesis of RSV-induced respiratory failure, which will facilitate her development as an independent investigator. Dr. Kong has a long track record of academic excellence and commitment to a research career. In her career development and research activities, Dr. Kong will be mentored by J. Edwin Blalock, Ph.D. and Amit Gaggar, M.D., who are recognized leaders in immunology, inflammation and protease biology. Dr. Kong has also assembled an advisory committee with expertise in the fields of inflammation, infectious disease and translational research (Drs. Rich Whitley, Namasivayam Ambalavanan, Eric Sorscher and JP Clancy), all of whom have given Dr. Kong their commitment to the successful completion of the proposed research aims, and in assisting her transition to being an independent physician-scientist. The University of Alabama at Birmingham (UAB) provides the ideal environment for training physician-scientists by combining state of the art research facilities, excellent career development resources and a broad clinical base. The fundamental hypotheses of this proposal are: 1) RSV is a potent stimulus of MMP-9 release from primary human airway epithelial cells, and that MMP-9 facilitates RSV propagation in airway epithelia through fusion protein proteolysis; 2) MMP-9 facilitates RSV infection and is a modulator of early viral-induced lung inflammation and injury; 3) MMP-9 activity is dysregulated in pediatric patients with RSV-induced respiratory failure, directly correlating with the generation of downstream chemotactic PGP fragments and clinical indicators of disease severity. The candidate's short-term goals during the period of this career development award is to complete the aims of this research plan, obtain a Master's degree in Biomedical Science in Clinical and Translational Science at UAB, present annually at scientific meetings and submit five or more peer- reviewed publications. In the latter half of the award period, she will submit an application for independen R01 funding. Her long-term goals are to develop an independent research program with the ultimate goal of identifying new biomarkers and creating novel therapies for RSV disease, based on an improved understanding of matrix destruction, airway and lung inflammation, with an emphasis host defense and host- pathogen interaction.

Public Health Relevance

Defining this protease-based signaling cascade in RSV-respiratory failure, including correlation with clinical measures of disease severity, coupled with identifying early events in RSV infection that generate MMP-9 may identify novel treatment avenues, potentially advancing disease management from support-based to strategic targeting of mediators that perpetuate lung inflammation and injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL119359-03
Application #
9054909
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Colombini-Hatch, Sandra
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pediatrics
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Gupta, Neha; Richter, Robert; Robert, Stephen et al. (2018) Viral Sepsis in Children. Front Pediatr 6:252
Randolph, Adrienne G; Yip, Wai-Ki; Allen, Emma Kaitlynn et al. (2017) Evaluation of IFITM3 rs12252 Association With Severe Pediatric Influenza Infection. J Infect Dis 216:14-21
Nye, Steven; Whitley, Richard J; Kong, Michele (2016) Viral Infection in the Development and Progression of Pediatric Acute Respiratory Distress Syndrome. Front Pediatr 4:128
Szul, Tomasz; Bratcher, Preston E; Fraser, Kyle B et al. (2016) Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes. Am J Respir Cell Mol Biol 54:359-69
Kong, Michele Y F; Whitley, Richard J; Peng, Ning et al. (2015) Matrix Metalloproteinase-9 Mediates RSV Infection in Vitro and in Vivo. Viruses 7:4230-53
Kong, Michele Y F; Whitley, Richard J; Peng, Ning et al. (2015) Addendum: Kong, M.Y.; Whitley, R.J.; Peng, N.; Oster, R.; Schoeb, T.R.; Sullender, W.; Ambalavanan, N.; Clancy, J.P.; Gaggar, A.; Blalock J.E. Matrix Metalloproteinase-9 Mediates RSV Infection in Vitro and in Vivo. Viruses 2015, 30, 7, 4230–4253. Viruses 7:5609
Kong, Michele Y F; Clancy, John P; Peng, Ning et al. (2014) Pulmonary matrix metalloproteinase-9 activity in mechanically ventilated children with respiratory syncytial virus. Eur Respir J 43:1086-96