Our research focuses on 3 major areas: (1) The role of transcription factor yin yang 1 (YY1) in Mn-induced repression of astrocytic glutamate transporters (GLAST and GLT-1) and excitotoxic neuronal injury; (2) Molecular mechanisms of RE1-silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF)-induced protection against Mn toxicity in astrocytes and dopaminergic neurons; and (3) The role of leucine rich repeat kinase 2 (LRRK2) and its genetic variants in Mn-induced neuroinflammation.
Project #1: Role of transcription factor yin yang 1 (YY1) in Mn-induced repression of astrocytic glutamate transporters (GLAST and GLT-1) and excitotoxic neuronal injury.
We use state-of-the-art technology, including Cre-loxP system and adeno-associated virus (AAV) vector injections to manuplate gene expression and deletion in specific brain tissues. This allows us to study the role of genes in our cells/tissue of interest, as well as examine unique neurotoxic and neuroprotective mechanisms.
Mouse model: astrocyte-specific YY1 knockout mice by crossing GFAP-Cre with YY1 loxP mice. This Cre-loxP technology allows us to study the role of YY1 in astrocytes in Mn neurotoxicity.
This project focuses on understanding the mechanisms of Mn-induced neurotoxicity associated with impairment of glutamate transporters. Impairment of astrocytic glutamate transporters is known to play a key role in the pathogenesis of various neurodegenerative diseases, including AD, PD, as well as manganism (caused by chronic exposure to Mn). Thus, getting insight into the role of glutamate transporters in manganism will shed light on neuroprotective strategies encompassing multiple neurodegenerative disorders.
We proposed a molecular mechanism model of Mn toxicity related to YY1 activation.
Project #2: Molecular mechanisms of RE1-silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF)-induced protection against Mn toxicity in astrocytes and dopaminergic neurons.
Transcription factor REST has been shown to exert neuroprotective effects in aging and AD patients as well as PD animal models. Our recent findings reveal that both Mn and YY1 repress REST in dopaminergic neurons and astrocytes, while estrogens enhance REST expression, suggesting that REST could be a potential molecular target to protect against Mn neurotoxicity as well as PD/AD.
Protective mechanisms of estrogenic compounds in Mn toxicity: 17beta-Estradiol (E2) and some selective estrogen receptor modulators (SERMs) such as tamoxifen (TX) and raloxifene (RX) have been shown to exert neuroprotection in various neurodegenerative diseases. Our findings demonstrate that these estrogenic compounds enhance expression of GLT-1 and REST. Thus, understanding the estrogen-induced modulatory mechanism of GLT-1 and REST is important to identify the molecular targets that can lead to develop neuro-therapeutics.
Project #3: The role of leucine rich repeat kinase 2 (LRRK2) and its genetic variants in Mn-induced neuroinflammation
The majority of PD cases are idiopathic, indicating that the etiology of PD is unknown. About 10 % of PD cases have been linked to a genetic cause, and mutations in the LRRK2 gene are the most common cause of genetic/familial PD. Intriguingly, genetic mutations of LRRK2 are significant risk factors for the development of sporadic PD and gene-environmental interaction associated with environmental toxins-induced neurotoxicity. We have found that LRRK2 mediated Mn-induced inflammation, and this effect was amplified in LRRK2 mutation, suggesting that there is an interaction between Mn and LRRK2. This study will shed light on understanding of the gene and environmental interplay for Mn as well as other potential environmental factors in inducing neurodegenerative diseases.
We are also interested in cancer research, particularly on epigenetic mechanisms and chemokines-associated inflammatory mechanisms in breast and pancreatic cancers in collaboration with other investigators