Research & Publications
A major goal of my research program is to obtain creative insights that advance knowledge in the field of Immune-Metabolic interactions that drive adiposity and age-related chronic diseases. Our studies focus on understanding the mechanisms and consequences of aberrant immune-cell activation in adipose tissue microenvironment and age-related ectopic adipocyte development in lymphoid microenvironment like thymus and bone marrow. This Laboratory utilizes basic cellular and molecular tools, genetic manipulations including reporter and Cre/Lox mouse models to understand patho-physiology of obesity and aging. In addition, clinical studies are evaluating the impact of caloric excess and caloric restriction on mechanism that impact inflammation and immune system. The long-term goal of our research is to understand the mechanisms of immune-metabolic crosstalk and to help develop novel approaches to regulate the aberrant immune cell activation as means to enhance healthspan.
Extensive Research Description
The NIH funded projects in the laboratory are –
R01AG043608: (National Institute on Aging)
Inflammasomes and the mechanism of thymic demise in aging.
The Nlrp3 inflammasome senses metabolic ‘danger signals’ and, upon assembly, causes caspase-1 activation, which in turn controls the secretion of pro-inflammatory cytokines IL-1β and IL-18. The central hypothesis of this proposal is that age-related thymic lipotoxicity via a canonical Nlrp3 Inflammasome-dependent mechanism induces ‘sterile thymic inflammation’ and induces T cell dysfunction during aging.
R01AI105097-01: (NIAID) Thymic adipogenesis and age-related thymic demise
With progressive aging, thymus is replaced with ectopic adipocytes and its ability to produce naïve T cells is dramatically diminished. This research project is designed to understand the lineage of adipocytes in aging thymus and to determine the causes and consequences of thymic adiposity and its relationship with immune-senescence.
P01AG051459: (NIA) Impact of FGF21 on healthspan and lifespan.
FGF21 is a unique metabolic hormone as it is secreted in blood from liver in response to starvation and nutrient deprivation to stimulate fatty acid oxidation and to maintain energy balance. Recent studies from our Program Project Team have demonstrated that overexpression of FGF21 in mice extends lifespan, improves insulin-sensitivity and may promote immune function. Based on these data, the central hypothesis of this program project is that FGF21 is a key driver of CNS-adipose tissue-immune system interactions that coordinately promote a pro-longevity molecular program. Overall objective of this project is to elucidate the molecular mechanisms underlying FGF21’s anti-aging effects and to leverage these insights towards inhibiting aging-related chronic diseases
R01AR070811-01. (NIAMS, NIH): Impact of ketones on inflammasome deactivation in Gout
Gout is caused by urate crystal deposition in the joints that cause severe inflammation, pain and joint destruction. There are currently few treatment options for Gouty flares which are episodes of severe pain. The main challenge to manage this disease is the inability to specifically block inflammasome. We have now found that body’s endogenous metabolite, typically produced upon fasting, called ketone body beta-hydroxybutyrate (BHB), can be harnessed to inhibit the inflammasome. The goal of this project to understand the mechanism of action of BHB on myeloid cells and to develop ketone bodies as potential therapeutic against Gout.
Public Health Interests
Aging; Immunology; Obesity