Reflections

  Specific aims Mechanistic target for rapamycin (mTOR) has recently emerged as central regulator of cell metabolism with key role in cell proliferation and cancer development.  Our investigation of human follicular thyroid cancer (FTC) tissue samples demonstrated activation of mTOR along with p-CREB. Our transgenic mouse model of human FTC by protein kinase A (PKA) activation (due to knockdown of the regulatory subunit PRKAR1A gene implicated as tumor suppressor in human FTC), faithfully replicated the human FTC results with activation of mTOR and p-CREB. Examination of signaling pathways in our mouse model, we interestingly found activation of AMPK (Thr-172) which is not only an energy sensor but also termed as negative regulator of mTOR pathway. However, AMPK is also essential to prevent cellular apoptosis in cells subjected to various kinds of stress. We therefore hypothesize that activation of both AMPK and mTOR pathways are essential, balancing the cellular metabolic pat...

  Targeting AMPK and mTOR pathways in Atopic Dermatitis Rationale Eczema or atopic dermatitis is chronic inflammation of the skin characterized by numerous relapses. Eczematous patches, plaques, epidermal edema along with immunological cells in the infiltrate are the histologic features of eczema. It has been shown recently that CD4 and CD8 T-cells and the inflammatory cytokines such as IFN-γ, TNF-α, play a dominant role in the pathology of atopic dermatitis. Recent literature also suggests using biologics targeted to counter these pro-inflammatory cytokines. However, recently more focus has been put towards understanding the metabolic pathways of T-cell activation. Particular focus has been put in understanding the fatty acid metabolism involved in the T-cells.  It has been shown that T-cell activation leads to increased glucose uptake and activation of PI3K/AKT and mTOR pathway. Utilization of fatty acids for energy needs, i.e. using beta oxidation on the other hand leads to...

Warburg's effect is quoted many times to describe the faulty metabolic pathways in tumor cells. Tumor cells which are rapidly dividing are known to create a hypoxic microenvironment which does not support glucose oxidation. Under these circumstances, glycolysis becomes a dominant metabolic pathway to generate energy for the rapidly dividing tumor cells. However, this may not be the complete story. In recent years, there has been a tremendous amount of work being done to explore the metabolic pathways involved in various tumors. All this now depicts a newer reality where glycolysis instead of being "The pathway" is now thought to be one of the pathways used by the tumor cells. Of interest are the protein metabolic pathways such as glutamine and proline pathways, The nucleic acid metabolic pathways and my present interest, the fatty acids pathways.  If we consider that alternative pathways such as fatty acid oxidation, protein metabolic pathways,  then all the proteins ...

Targeting AMPK and mTOR pathways in Eczema   Rationale Eczema or atopic dermatitis is chronic inflammation of the skin characterized by numerous relapses. Eczematous patches, plaques, epidermal edema along with immunological cells in the infiltrate are the histologic features of eczema. It has been shown recently that CD4 and CD8 T-cells and the inflammatory cytokines such as IFN-γ, TNF-α, play a dominant role in the pathology of atopic dermatitis. Recent literature also suggests using biologics targeted to counter these pro-inflammatory cytokines. However, recently more focus has been put towards understanding the metabolic pathways of T-cell activation. Particular focus has been put in understanding the fatty acid metabolism involved in the T-cells.  It has been shown that T-cell activation leads to increased glucose uptake and activation of PI3K/AKT and mTOR pathway. Utilization of fatty acids for energy needs, i.e. using beta oxidation on the other hand leads to...