Research Interests:

• B lymphocyte physiology and pathology
• Immunoglobulin genes, including surrogate light chain (Psi LC) structure and function
• Antigen (Ag)-dependent B lymphocyte maturation and selection
• Regulation of cell survival and apoptosis

Coordinate regulation of co-stimulatory B cell signaling: My lab discovered AKNA, an AT-hook DNA-binding protein that is selectively expressed by B and T lymphocytes, natural killer cells (NKC) and dendritic cells (DC). We have demonstrated that AKNA is present in the nucleus, can coordinately bind to CD40 and CD40 ligand (CD40L/ CD154) promoters and regulate the expression of the receptor and its ligand. The specific aims of this program are: (i) To assess in vitro the role of AKNA in gene transcription, using molecular and biochemical approaches; (ii) To examine whether AKNA plays any role in CD40-dependent maturation and function of other antigen presenting cells (APC) such as DC, by retroviral transduction of primary progenitor cells and adoptive transfer methods; (iii) To assess in vivo the significance of AKNA’s function, by the generation of genetically engineered mice, in which AKNA expression is constitutively overexpressed (Tg) or has been inactivated (KO).

Control of B lymphocyte survival and death. This program focuses on PRELI, an evolutionarily conserved mitochondrial protein also discovered in my lab, which can protect cells from programmed death. We have shown that PRELI possesses tandem repeats of the LEA (late embryogenesis abundant) motif and can abrogate apoptosis induced by diverse stimuli. Our data demonstrates that PRELI is the antagonist of AIF, which is the major mediator of capsase-independent apoptosis. The relevance of PRELI as a suppressor of apoptosis has been substantiated by two targeted perturbations of its function: (a) deletion of its functional LEA motif and (b) siRNA silencing in human cells. The specific aims of the program are: (i) To assess the mechanisms behind PRELI-dependent control of apoptosis , including effects on the respiratory chain, reactive oxygen species (ROS) production and Ca 2+ fluxes. These studies also aim to assess putative interactions of PRELI with other proteins , by genetic and biochemical methods, including protein-profiling screens and yeast two-hybrid analysis; (ii) To assess in vivo the effects of PRELI gene overexpression and inactivation . We are generating two distinct mouse models: (a) Tg mice in which the overexpression of PRELI under the control of the Mu enhancer (E Mu) is targeted to the B cell compartment. (b) B cell-specific PRELI-deficient mice is underway to investigate the consequences of the inactivation of its gene on B lymphocyte survival.

Publications

Program Affiliation:

Program in Immunology