Research

Research

Adult neurons are crucial and precious cell types controlling human body functions. Neuron injury following stroke or other neurologic diseases causes a significant loss of function. Our goal is to understand the molecular mechanisms how neurons die following acute brain injury as well as neurodegenerative diseases and develop novel therapeutic strategies to prevent or delay neuron death.

Poly(ADP-ribose) polymerase-1 (PARP-1) is an important nuclear enzyme that facilitates DNA repair. However the excessive activation of PARP-1, which could be induced either by DNA alkylating agent MNNG or overactivation of glutamate receptors, causes cell death (Fig. 1a). PARP-1 plays a pivotal role in DNA damage (Fig1 b&c) and glutamate neurotoxicity following ischemic brain injury as well as neurodegenerative diseases.

Fig 1 Wang Lab
Fig. 1: PARP-1 dependent cell death

PARP-1 deficient cells are strongly resistant to MNNG-mediated cell death (Fig. 2) and PARP-1 knockout mice are resistant to stroke.

PARP-1 knockdown prevents MNNG-induced cell death
Fig. 2: PARP-1 knockdown prevents MNNG-induced cell death

Release of mitochondrial flavor protein apoptosis inducing factor (AIF) and translocation to the nucleus leads to chromatinolysis, which is the commitment point for PARP-1-dependent cell death (parthanatos) (Fig. 3).

Signaling pathway of PARP-1-dependent cell death (parthanatos)
Fig. 3: Signaling pathway of PARP-1-dependent cell death (parthanatos)

Dr. Wang's lab uses a combination of tools, including epigenetics, bioinformatics, proteomics and mouse genetics (Fig. 4-5), to study the cell signaling and regulation of PARP-1-dependent DNA damage and neuron death in neurologic diseases.

Protein Chip high throughput screen
Fig. 4: Protein Chip high throughput screen
NMDA and AAV-ICV injection in vivo
Fig. 5: NMDA and AAV-ICV injection in vivo