Seven out of ten top leading causes of mortality in the developed world (from atherosclerosis and heart disease to diabetes and cancer) share a common pathology: chronic inflammation. Diagnosis is often made when the damage to critical organs is already significant and irreversible because none of the existing inflammation markers is appropriate for early detection of chronic inflammation conditions. To change the status-quo, we will rely on emerging knowledge proposing new roles for neutrophils - the typical innate immune cell to protect us against microbes - in chronic inflammation. Observations in transgenic animals showed that some neutrophils are capable of reversing migration from tissues to circulation after responding to a sterile injury. Recently, we have been able to replicate the reversed-migration patterns in a novel in vitro device. The major goal of this proposal is to continue improving the design of these devices, to identify and characterize the modulators of reversed-migration in vitro, and to design more sophisticated technologies that can separate the neutrophils undergoing reversed migration, for subsequent genomic and proteomic analysis. These tools would enable us to characterize the reversely-migrated neutrophils in detail and to identify specific markers that could differentiate the reversely-migrated neutrophils from naive neutrophils in blood samples from patients with chronic inflammation. If successful, our research could lead to new methods for monitoring chronic inflammation, could enable early diagnosis, allow sufficient time to adopt lifestyle changes, assist early treatments, and could have major implications for reducing morbidity and mortality associated with chronic inflammation diseases.

Public Health Relevance

Chronic inflammation is the pathology responsible for seven of the top ten leading causes of mortality in the developed world, from atherosclerosis and heart disease to diabetes and cancer. Neutrophils, the white blood cells involved in protecting us against microbes, have been recently shown to participate in the initiation, tissue damage, and persistence of chronic inflammation. To better understand this pathology, we propose to develop novel microfluidic tools that will enable the study in vitro of the newly discovered migration patterns that return neutrophils from tissues into circulation, which could ultimately become a maker for ongoing chronic inflammation processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI113937-02
Application #
9096701
Study Section
Enabling Bioanalytical and Imaging Technologies Study Section (EBIT)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2015-06-24
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Ellett, Felix; Jorgensen, Julianne; Marand, Anika L et al. (2018) Diagnosis of sepsis from a drop of blood by measurement of spontaneous neutrophil motility in a microfluidic assay. Nat Biomed Eng 2:207-214
Wang, Xiao; Jodoin, Emily; Jorgensen, Julianne et al. (2018) Progressive mechanical confinement of chemotactic neutrophils induces arrest, oscillations, and retrotaxis. J Leukoc Biol 104:1253-1261
Ellett, Felix; Irimia, Daniel (2017) Microstructured Devices for Optimized Microinjection and Imaging of Zebrafish Larvae. J Vis Exp :
Chandrasekaran, Arvind; Ellett, Felix; Jorgensen, Julianne et al. (2017) Temporal gradients limit the accumulation of neutrophils towards sources of chemoattractant. Microsyst Nanoeng 3:
Frydman, Galit H; Le, Anna; Ellett, Felix et al. (2017) Technical Advance: Changes in neutrophil migration patterns upon contact with platelets in a microfluidic assay. J Leukoc Biol 101:797-806
Hamza, Bashar; Irimia, Daniel (2015) Whole blood human neutrophil trafficking in a microfluidic model of infection and inflammation. Lab Chip 15:2625-33