The projects in our lab are focused on understanding neurodevelopmental, neuropsychiatric and neurodegenerative diseases such as autism spectrum disorder, major depressive disorder, Parkinson’s disease and Alzheimer’s disease. We are particularly interested in these diseases because they exhibit two critical components: deregulation of immune responses and sex dimorphisms. More specifically, we study how sex hormone NRs, such as estrogen receptor (ERα and ERβ) and androgen receptor (AR), mediate transcriptional and epigenetic changes in microglia that regulate overall immune responses in the brain. Through the use of mouse models, we hope to develop novel, NR-based therapeutic strategies for the treatment of neurological diseases.
Diseases with male bias
Autism Spectrum Disorder (ASD)
ASD is a collection of complicated neurodevelopmental disorders that are characterized by impaired social abilities, defective learning and memory, and repetitive restricted behaviors. Both genetic and environmental factors play roles in the pathogenesis of ASD. In particular, prenatal and neonatal immune activation are suggested to be important environmental factors. Therefore, we are using prenatal inflammation-induced mouse models of ASD to test whether prenatal infection alters microglial function and synaptic pruning during brain development, leading to autistic behaviors. In addition, recent genome-wide association studies (GWAS) have revealed that many transcriptional and epigenetic regulators, including ER and AR themselves, are mutated in ASD patients. We hypothesize that these factors play essential roles in controlling microglial functions in the developing brain. Using prenatal inflammation-induced models of ASD, we are testing whether prenatal infection alters microglial function and synaptic pruning during brain development, leading to autistic behaviors. We are also testing our hypothesis by expressing the identified mutants specifically in microglia in order to determine whether they are sufficient to induce autistic behaviors in mice.
Parkinson’s Disease (PD)
PD is one of the most common age-dependent neurodegenerative diseases and is characterized by tremors, bradykinesia and rigidity. The hallmarks of PD pathology are the loss of dopaminergic neurons in the substantia nigra, accumulation of intracellular protein aggregates (Lewy bodies), and inflammation. Interestingly, polymorphisms of ERβ and interleukin (IL)-6 are known to associate with increased risks of PD. Our results have shown that a subset of androgens can function as endogenous ERb ligands, resulting in the repression of pro-inflammatory mediators, including IL-6, IL-1b, and iNOS. Therefore, we hypothesize that aging impairs the production of anti-inflammatory ERβ ligands in microglia and that the subsequent loss of ERβ-mediated repression of inflammation plays a critical role in the development of PD. Currently, we are working on testing our hypothesis using the LPS-induced PD mouse model in order to understand the mechanistic correlation between ERβ, inflammation and PD.
Diseases with female bias
Alzheimer’s Disease (AD)
AD is the most common age-dependent neurodegenerative disease and its major symptoms include progressive loss of memory and cognitive impairment. Several genes are identified as being responsible for familial AD, however, the majority of cases are sporadic, suggesting that environmental factors play essential roles in AD pathogenesis. In particular, aging and diet may be critical environmental factors for inducing AD pathology. As women get older, the age-dependent reduction of estrogens during menopause may decrease the ligand-dependent recruitment of corepressors to ERs, resulting in increased susceptibility to neuroinflammation and development of AD. Type 2 diabetes mellitus (T2DM) has also been shown to significantly increase the risk of AD, suggesting that diet is an important factor for AD pathogenesis. T2DM is characterized by insulin insensitivity and is triggered by pro-inflammatory macrophages migrating into adipose tissue. However, the mechanisms underlying how T2DM increases the risk of AD are not understood. Since a high fat diet is sufficient to induce brain inflammation and macrophages express ERα, we are using mouse models to test whether systemic administration of various endogenous estrogens can repress macrophage-dependent inflammation and improve insulin sensitivity, resulting in decreased brain inflammation and prevention or amelioration of AD symptoms.
Major Depressive Disorder (MDD)
Estrogen levels and an increased risk of MDD are closely correlated. For example, women during pregnancy, delivery, nursing (maternity blues) and post-menopause are at high risk for developing MDD, suggesting the importance of estrogen-mediated regulation. Recent GWAS results suggest that genes regulating immune responses, synaptic function and histone methylation are mutated in patients with adult psychiatric diseases. Since pro-inflammatory cytokines are sufficient to induce depression in animal models, we are testing the hypothesis that inflammation and changes in the levels of sex hormones influence microglial functions in the adult brain, leading to malfunctions in neurons and depressive behavior.