David Vaux - Research Projects

David Vaux - Research Projects


Determining the mechanism of lymphocyte apoptosis induced by glucocorticoids

In the mouse thymoma cell line WEHI-7, Flomerfelt and Miesfeld (JCB 1994) showed that there are at least six unique genes required for them to undergo apoptosis following treatment with dexamethasone. While they showed that the first gene in the path was the glucocorticoid receptor, they were not able to identify the other genes. We are re-visiting this system, using CrispR technology to identify the genes involved.

Regulation of autophagy by Bcl-2

We found that Bcl-2 is unable to inhibit autophagy in cells that lacked Bax and Bak, but when Bax and Bak were present, autophagy occurred as cells underwent apoptosis. This indicates that when activated, Bax and Bak can directly or indirectly promote autophagy.

We are seeking to determine the molecular pathway by which autophagy is induced in cells undergoing apoptosis. 

Regulation of cell size and proliferation in the absence of apoptosis

Unlike their wild type parents, lymphoid (WEHI-7) and myeloid (FDM) cell lines lacking genes for Bax and Bak do not undergo apoptosis when treated with steroids or starved of IL-3. They shrink, arrest, and persist for weeks in a quiescent state.

These cells do not require autophagy, proteasome activity or protein synthesis to survive.

We wish to determine the mechanism for this arrest using CrispR screens, RNAseq, and CHIPseq.

These arrested cells are resistant to many chemotherapeutic agents. A drug that blocked this arrest might restore sensitivity to allow chemotherapeutic agents to kill cancer cells.

How does dexamethasone block cytokine growth signals?

Normally, factor starved arrested Bax/Bak deleted FDMs grow and proliferate as soon as IL-3 is added.

In contrast, FDMs arrested with dexamethasone do not grow and proliferate when IL-3 is added.

We wish to determine the mechanism by which the glucocorticoid receptor blocks signaling pathways activated by cytokines.