P01HL152953

Air Pollution Disrupts Inflammasome Regulation in Heart and Lung Total Health (AIRHEALTH) - Abstract:

Overall component exposure to air pollution from automobile exhaust and forest fires is a significant, rapidly growing global public health burden that contributes to cardiopulmonary pathogenesis. Produced by epithelial and inflammatory cells, interleukin-1 beta (IL-1β) is key to this inflammatory response within blood, lung, cardiac, and vascular tissues, and primarily associated with acute and chronic inflammation upon exposure to pollutants.

Accordingly, understanding the mechanisms of IL-1β and other pathways will significantly benefit cardiopulmonary health since therapies are available to block this pathway and since knowledge of direct mechanisms of how air pollution leads to cardiopulmonary diseases is needed to shape policy in public health.

Our central objective is to test distinct but intertwined mechanistic aspects of IL-1β and other pathway regulation in inflammation-associated cardiopulmonary pathology linked to air pollution. We will test the hypothesis that the immunopathology of cardiovascular and pulmonary diseases are linked to IL-1β and/or other pathways, as we have preliminary data demonstrating activation of IL-1β and inflammasome, and other pathways in air pollution exposure, particularly PM2.5. We understand there are other pathways other than IL-1β involved and to this end, we have proposed unbiased, agnostic experiments in all projects and cores, especially the systems biology approach of Project 2.

Furthermore, our data show the link of immune pathways to clinical outcomes, such as increased systolic blood pressure, in young children and adolescents exposed to air pollution. We have created synergy and dependency of all the projects and cores since we use all the same samples from the same cohorts, we share data to be able to create composite biological biomarkers to link pathology to disease (i.e. asthma or increased blood pressure). As an example of our innovation together, we have proposed using induced pluripotent stem cells (iPSCs) in both lung and heart models (Projects 1 and 3) to screen and identify agents that block IL-1β and other pathway effects.

Our aims are:

1. Describe the mechanisms underlying heart, lung, and immune diseases associated with air pollution (PM2.5) exposure. We will identify and characterize biomarkers of acute and chronic environmental exposure to air pollution that predict cardiopulmonary diseases.

2. Ensure the efforts of the three scientific projects and project cores will be synergistic, coordinated, and integrated. We describe specifically how the three projects and cores are synergistic and how we will integrate our study findings with other efforts to investigate IL-1β and other pathways.

3. Provide a highly interactive, collaborative, and multi-disciplinary team of investigators and resources to support our goals. We describe our multi-disciplinary facilities and investigators that will contribute to the overall success of the PPG, called AIRHEALTH.

If our program and overall aims are met, we will define the mechanistic links of lung and heart diseases with IL-1β and other pathways, which will likely lead to clinical application of biologicals and other drugs in individuals exposed to acute and/or chronic air pollution.

President And Fellows Of Harvard College

NOT APPLICABLE

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Boston, Massachusetts 021156028 United States

Single Zip Code

NHLBI Program Project Applications (P01 - Clinical Trials Optional) (PAR-18-405)

Amendment Since initial award the total obligations have increased 271% from $2,139,001 to $7,936,342.