Research

Basic Science

1. Ovarian Development and Primary Ovarian Insufficiency

Germ cells carry the history of our generation(s), are unique in their biology and are of utmost importance in propagation and causation of genetic disorders. Their uniqueness is also reflected in special mechanisms and molecules that govern their differentiation and growth. Our lab is particularly interested in understanding the transcriptional regulation of ovarian follicle activation and oocyte survival.

Early stages of ovarian follicle formation, beginning with the breakdown of germ cell cysts, the formation of primordial follicles, and transition to primary and secondary follicles, are critical in determining the reproductive life span and fertility. Transcription of numerous germ cell-specific genes necessary and essential for follicular development is initiated during these early stages of follicle formation. These transcription factors are necessary to drive oocyte growth and synthesis of maternal effect genes that determine early embryogenesis and are likely involved in the setting of epigenetic marks. We discovered novel germ cell-specific transcriptional regulators Sohlh1, Sohlh2, Lhx8, and Nobox. We also discovered that mutations in oocyte-specific transcriptional regulators such as Nobox and Figla associate with premature ovarian failure, emphasizing the importance of these pathways to women’s health. Our lab is additionally interested in studying MCM8 and MCM9.

Sohlh1 and Sohlh2 are basic helix-loop-helix transcriptional regulators that suppresses primordial follicle activation (PFA), and Sohlh1 and Sohlh2 deletions cause rapid PFA and oocyte loss. LHX8, a highly conserved LIM homeodomain protein, is located downstream of SOHLH1 and SOHLH2, and also represses primordial follicle activation. SOHLH1, SOHLH2 and LHX8 are uniquely expressed in the germline, and their deficiency affects gonadal development. We are exploring the various effects of these genes within mouse models in our laboratory.  

MCM8 and MCM9 are members of the minichromosome maintenance (MCM). These are autosomal genes that have been implicated in causing hypergonadotropic hypogonadism in an autosomal recessive pattern. Female mice with defects in MCM8 and MCM9 are infertile, with early loss of germ cells and a high predisposition to hepatocellular carcinoma and ovarian tumors. It is also suggested that this gene may strongly correlate with menopause. We have developed mouse models in our lab to study the fertility of these mice and understand their effect on female infertility and aging.

In addition to uncovering mechanisms of oogenesis, we are interested in exploiting tissue-specific pathways to modulate fertility and reproductive life span and measure ovarian reserves. We are specifically interested to identify novel biomarkers of primordial follicle reserves as well as tissue-specific targets to control reproductive life span.   

2. Uterine leiomyomas

Uterine leiomyomas, better known as fibroid tumors, are clinically apparent in nearly 25% of women by age 45, and they cause major morbidity in American women. More than 200,000 surgeries are performed each year to either remove the leiomyomatous tumors (myomectomy) or the entire uterus (hysterectomy). Approximately half of all leiomyomas are asymptomatic, while the rest cause pelvic pressure and pain, irregular and heavy bleeding, anemia, premature labor, and infertility. These symptoms are intensified by the common occurrence of multiple tumors within a single uterus, often necessitating surgical intervention. We have discovered microdeletions and duplications that associate with this tumor as well as that mutations within one gene, Med12, are present in as many as 70% of women with leiomyomas. We are currently investigating the mechanisms of Med12 action in leiomyomas and therapies directed towards eliminating such tumors in symptomatic women.