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Thackray Lab Research Interests
 
 
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women with a prevalence of 10-15%.  In addition to a reproductive phenotype that results in an increased risk of infertility, miscarriage and pregnancy complications, ~80% of PCOS women have metabolic abnormalities that result in an increased risk of type 2 diabetes, cardiovascular disease and non-alcoholic fatty liver disease. One of the main objectives of our research is to understand the etiology and pathophysiology of PCOS using relevant mouse and tissue culture models.

  

Genetic Influences on FSH Production


One of our research projects is focused on single nucleotide polymorphisms (SNPs) near the FSHB gene that are associated with an increased risk of developing PCOS in genome-wide association studies (GWAS). This research is currently funded by an NIH/NICHD P50 grant (HD012303). We are interested in understanding mechanisms involved in regulating FSH production by the G/T SNP at ‑211 relative to the transcription start site of the human FSHB promoter (rs10835638). We previously reported that the LHX3 homeodomain transcription factor binds to an 11 bp element in the human FSHB promoter which includes the -211 nucleotide. We also demonstrated that LHX3 bound with greater affinity to the wild-type human FSHB promoter compared to the ‑211 G/T mutation and that FSHB transcription was decreased in gonadotrope cells with the ‑211 G/T mutation compared to the wild-type FSHB promoter. We are currently studying how this SNP and other SNPs upstream of FSHB regulate FSH production using tissue culture and mouse models. Comprehending these mechanisms may be useful for the development of novel diagnostic tools for infertility or infertility treatments in order to tailor fertility treatments appropriately to each patient to maximize the success rate and minimize side effects of fertility drugs.


Influence of the Gut Microbiome on the PCOS Metabolic Phenotype

 

Another focus of our research is to investigate the role of the intestinal microbial community (gut microbiome) in the etiology and development of the PCOS metabolic phenotype.  This research is currently funded by an NIH/NICHD R01 grant (HD095412). While the gut microbiome is perturbed in individuals with obesity or type 2 diabetes, it is unknown whether an altered microbiome influences the development or pathophysiology of PCOS. We recently demonstrated that there are significant changes in the composition of the gut microbiome in women with PCOS and in a letrozole-induced PCOS mouse model compared to controls. We also demonstrated that these changes in the gut microbiome are associated with increased levels of testosterone. We are currently investigating mechanisms involved in the alteration of the gut microbiome in the PCOS mouse model using metagenomic sequencing, metabolomics and metabolic analyses. Understanding the role of the gut microbiome in PCOS may provide important insight into the pathology of the metabolic phenotype that occurs in women with PCOS and the development of novel treatment options for this disorder, including pre- or probiotic therapies.