# NLRP3 Inflammasome Activation and Mitochondrial Function in the setting of Aging and HIV Infection

> **NIH NIH K76** · YALE UNIVERSITY · 2022 · $226,556

## Abstract

Project Summary/Abstract:
Both the aging and the aging HIV-infected population are characterized by increased rates of metabolic
syndrome (defined by abdominal obesity, dyslipidemia, insulin resistance and hypertension). Notably,
metabolic syndrome is associated with the dysregulated, age-associated pro-inflammatory environment—
termed “Inflamm-aging”—characterized by elevated levels of cytokines, acute phase reactants, and clotting
factors. Chronic stimulation of innate immune receptors by both pathogen-associated molecular patterns
(PAMPs) and damage associated molecular patterns (DAMPs) is thought to contribute to age-associated
chronic inflammation, but the mechanisms underlying the pathogenesis of metabolic syndrome in the context
of aging and HIV disease remain an incompletely understood knowledge gap in the field. The NLRP3 (NOD-
like receptor pyrin domain-containing 3) inflammasome is an intracellular protein complex, that is part of the
innate immune response and mediates the caspase-1-dependent cleavage of pro-IL-1b and pro-IL-18 to their
activated forms. While the NLRP3 inflammasome is activated by PAMPs, there is increasing evidence for a
role of NLRP3 as a sensor of host metabolism via DAMPs, as shown by NLRP3 activation by a wide range of
metabolites. Moreover, NLRP3 inflammasome activation is dependent on mitochondrial function. The NLRP3
inflammasome has been linked to the development of insulin resistance and other metabolic syndromes in
mouse models, and has been minimally explored in both older adults and HIV-infected adults. The purpose of
this proposal is to determine the effects of age and HIV infection on the NLRP3 inflammasome, and its
relationship with mitochondrial function by comparing the following groups of subjects, young adults (21-35),
and older adults (≥ 60 yrs) with and without HIV-infection. Aim 1 seeks to characterize the NLRP3
inflammasome and its relationship with mitochondrial function, in myeloid cells from peripheral blood and
adipose tissue. Aim 2 seeks to characterize the metabolic pathways that are induced with activation of the
NLRP3 inflammasome through RNA sequencing and CyTOF in myeloid cells from peripheral blood and
adipose tissue. Data from both aims will be collected in conjunction with clinical characteristics including the
components of metabolic syndrome. Our hypothesis is that increased age and HIV infection will result in
dysregulated NLRP3 inflammasome function at baseline and with activation that is linked to
mitochondrial dysfunction—ultimately contributing to the development of metabolic syndrome in older and
HIV-infected adults. The candidate, Dr. Zapata is an Infectious Disease physician at the Yale school of
medicine, who has put together an interdisciplinary mentorship committee with expertise in immunology, aging,
and metabolism. This training proposal is coupled with a career development plan that includes mentorship
and didactic training in Immuno-metabolism, with an additional f...

## Key facts

- **NIH application ID:** 10433974
- **Project number:** 5K76AG064548-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Heidi J Zapata
- **Activity code:** K76 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $226,556
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433974

## Citation

> US National Institutes of Health, RePORTER application 10433974, NLRP3 Inflammasome Activation and Mitochondrial Function in the setting of Aging and HIV Infection (5K76AG064548-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10433974. Licensed CC0.

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