Myocarditis caused by viral infections is a leading cause of sudden death and can progress to dilated cardiomyopathy (DCM) and the need for a heart transplant. Currently, there are no disease-specific therapies to reduce myocarditis or prevent progression to DCM. Toll like receptor 4 (TLR4) is known to promote viral myocarditis, triggering proinflammatory cascades that promote acute heart failure and progression to DCM. Thus, there is a need to develop novel therapies that suppress TLR4-driven inflammation to ameliorate myocarditis. Recent studies have indicated that adipose-derived stem cells (ADSCs) have anti-inflammatory effects that are mediated by cell-secreted biogenic nanoparticles (BiNPs). However, the immunomodulatory properties of heterogeneous adipose tissue-derived BiNPs have not been explored. Our preliminary results indicate that adipose tissue-derived BiNPs: (i) suppress TLR4-induced inflammatory responses in macrophages, (ii) reduce inflammation and TLR4 expression in a mouse model of viral myocarditis, (iii) take less time to process, cost less to obtain, and are more abundant compared to cell culture-derived BiNPs, and (iv) can be loaded with conventional drugs that further enhance anti-inflammatory effects. We hypothesize that adipose-derived BiNPs reduce TLR4-induced activation of inflammation in the heart and can be used to treat myocarditis and DCM. To test this hypothesis, we will determine the mechanism of patient-derived lipoaspirate- derived BiNPs (Lipo-NPs) in a mouse model of myocarditis/ DCM (Aim 1), and assess the performance of patient-derived Lipo-NPs as drug delivery vehicles for anti-inflammatory compounds in a mouse model of myocarditis (Aim 2), measuring the biodistribution of Lipo-NPs in healthy and male and female mice with myocarditis and determining the effect of Lipo-NPs loaded with anti-inflammatory agents on myocarditis by sex. We will utilize our laboratory's expertise in BiNP isolation along with a well-characterized murine viral myocarditis/ DCM model. We anticipate that this study will delineate the role of adipose BiNPs in myocarditis/ DCM and potentially lead to new clinically relevant therapeutic strategies.

Public Health Relevance

Toll like receptor 4 is known to promote viral myocarditis, triggering proinflammatory cascades that promote acute heart failure and progression to dilated cardiomyopathy. The proposed project will assess therapeutic anti-inflammatory effects of adipose-derived biogenic nanoparticles. Discoveries from this study will be important for advancing treatment and prevention strategies for myocarditis, as current options are limited to supportive care.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI152318-02
Application #
10089412
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Liu, Qian
Project Start
2020-02-01
Project End
2022-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224