Research

Exploring vitamin D signaling in metabolism and physiology

Shift to carbohydrate based diet during weaning of VDRKO mice leads to glycogen accumulation in skeletal muscles

Continuing on diets with higher fats restores growth and prevents cachexia in these mice. We showed that vitamin D signaling becomes essential during the metabolic shift that happens during weaning!

(Das et al., 2002, 2003)

Immune metabolism

Th2 cells are susceptible to mitochondrial ribosome-targeting antibiotics

Mitochondria are the organelles present in all eukaryotic cells whose primary responsibility is to generate energy. The mitochondrial genome codes for 13 genes that are translated by mitochondrial ribosomes, which resemble bacterial ribosomes than their cytosolic counterparts.

A large class of antibiotics, commonly used during infections target bacterial ribosomes, and many of these inhibit mitochondrial ribosomes as well. Activated immune cells such as T cells depend on their mitochondrial activity to suppress infection.

We asked how the antibiotics that inhibit mitochondrial translation affect T cell activation and differentiation using chloramphenicol. Recently other studies have shown that such antibiotics affect the effects function of T cells, which we also observed in our study.

Apart from this general inhibition of T cell function, Th2 cells, a subclass of T cells that are involved in allergies and essential for the control of helminth infection, undergo increased apoptosis when subjected to chloramphenicol during activation compared to Th1 cells.

On the other hand, when activated in the presence of 2-deoxyglucose, an inhibitor of glycolysis, Th1 cells exhibited higher apoptosis compared to Th2 cells. These differential effects of OXPHOS and glycolysis inhibition on Th1 and Th2 hold for mouse and human T cells.

This phenomenon reveals a fundamental difference in the metabolic properties of these two subsets of T cells: Th1 cells depend more on glycolysis for survival while Th2 cells depend more on OXPHOS.

Functional Genomics

To understand the systemic metabolism under chronic conditions, it is vital to establish the changes in gene expression different organ systems. We have developed extensive bioinformatics skill sets to analyse various types of functional genomics data including RNAseq, Riboseq, ATACseq, single cell RNAseq, and single cell ATACseq. We collaborate extensively with other laboratories who are interested in out bioinformatics tools.

Though mature adaptive immune cells are in a quiescent state with minimal metabolic activity. Activation of these cells with specific antigens leads to dramatic changes in the gene expression and metabolism of these cells, which finally enables the organism to mount a proper immune response. We have shown that the energy and protein metabolism of resting B and T cells vary significantly, with implications in their post-activation functions: B cell protein synthesis poises these cells for immediate antigen processing and presentation. The crosstalk between gene expression and the metabolism of resting as well as activated lymphocytes are not well understood.

We are currently addressing the following questions:

How the initial differences in the protein homeostasis and energy metabolism of B and T cells are established, and what are the functional consequences of these differences?
How the metabolic changes in the activated lymphocytes cells modulate gene expression in these cells. We are focusing on the mitochondrial translation and an important regulator of lymphocyte activation and differentiation.

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