During the last century, our society has changed dramatically, and today more than 20% of the population works odd hours, travels across time zones, and has disrupted sleep patterns. These are all factors affecting circadian rhythms and that lead to medical illnesses including cardiovascular disease, diabetes, decreased cognitive capacity, and impaired fertility. Female fertility is particularly sensitive to compromised circadin rhythms causing dysregulation of the hypothalamo-pituitary-gonadal (HPG) axis. Formation of the suprachiasmatic nucleus (SCN) is a fundamental step in the establishment of circadian rhythms, and is required for fertility. The SCN orchestrates the HPG axis by coordinating gonadotropin-releasing hormone (GnRH) neuron activity with peripheral tissues and light cycles. Mature GnRH neurons release GnRH in a pulsatile fashion maintaining basal levels of sex steroids and the preovulatory LH surge. Compromised fertility due to abnormal GnRH and SCN function can arise during development by genetic mutations or in adulthood by disrupted SCN function as caused by disrupted sleep patterns. I have developed novel mouse models and functional assays that will allow me to address the relationship between altered GnRH and SCN neuron function during development or in adulthood, and how these relate to fertility. I have identified the homeoprotein Ventral Anterior Homeobox 1 (VAX1) as required for SCN and GnRH neuron development, and specific deletion of Vax1 compromises fertility. In the SCN, VAX1 is necessary for expression of the core SCN transcription factor, SIX homeobox 3 (SIX3). I show that deletion of Vax1 or Six3 in mature neurons affects circadian locomotor activity, leading to abnormal estrous cyclicity and subfertility. The overarching hypothesis is that the homeodomain transcription factor VAX1 is essential for fertility due to its importance during development for GnRH neuron and SCN maturation, and in adulthood for modulating rhythms.
Aim 1 will examine the mechanism by which VAX1 determines GnRH neuron fate during development, and investigate the importance of VAX1 in mature GnRH neurons for rhythm generation.
Aim 2 will address the importance of VAX1 and SIX3 in SCN function and how disrupted rhythm generation impacts circadian behavior and fertility.
Aim 3 will investigate the cascade of homeodomain proteins in SCN development, and their role in SCN pacemaker function. The ultimate goal is to identify therapeutical targets for rhythm abnormalities. I believ these studies will provide valuable insight into novel mechanisms of regulation of fertility, and determine the association between rhythm generation and reproductive function in both GnRH neurons and the SCN. This multifaceted, interdisciplinary approach should yield a comprehensive understanding of the importance of VAX1 in GnRH neuron maturation and function in adulthood and the significance of complete maturation and correct function of the SCN in fertility. This is an ideal pathway to independence supported by an exceptional group of mentors, extensive novel training, a world class scientific environment, and clear departmental commitment.

Public Health Relevance

Fertility relies on coordinated rhythms in the central nervous system and the periphery. Impaired circadian rhythms, as seen in subjects with genetic mutations, or in shift work and stressful situations, leads to inappropriate hormone release, negatively impacting normal reproductive function. Restoration of circadian rhythms by alignment of the internal rhythm in the body to the time of day restores fertility, thus, identification of molecules modulating circadian rhythms will reduce the negative impact on health of disrupted circadian rhythms and restore fertility.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Ravindranath, Neelakanta
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Michigan State University
East Lansing
United States
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