The Role of the Homeoprotein Vax1 in Fertility and Circadian Rhythm

 描述（由申请人提供）：在上个世纪，我们的社会发生了巨大的变化，今天超过20%的人口在奇怪的时间工作，跨越时区旅行，并扰乱了睡眠模式。这些都是影响昼夜节律的因素，并导致医疗疾病，包括心血管疾病，糖尿病，认知能力下降和生育能力受损。女性生育能力对导致下丘脑-垂体-性腺（HPG）轴调节异常的昼夜节律受损特别敏感。视交叉上核（SCN）的形成是建立昼夜节律的基本步骤，并且是生育所必需的。SCN通过协调促性腺激素释放激素（GnRH）神经元活动与外周组织和光周期协调HPG轴。成熟的GnRH神经元以脉冲方式释放GnRH，维持性类固醇的基础水平和排卵前LH峰。由于GnRH和SCN功能异常而导致的生育能力下降可能会在发育期间因基因突变而出现，或者在成年期因睡眠模式中断而导致SCN功能中断而出现。我已经开发了新的小鼠模型和功能测定，这将使我能够解决在发育过程中或成年期GnRH和SCN神经元功能改变之间的关系，以及这些与生育力的关系。我已经确定了SCN和GnRH神经元发育所需的同源异型蛋白质大脑前同源异型盒1（VAX 1），VAX 1的特异性缺失会损害生育能力。在SCN中，VAX 1对于核心SCN转录因子SIX同源框3（SIX 3）的表达是必需的。我发现，成熟神经元中Vax 1或Six 3的缺失会影响昼夜运动活动，导致异常的发情周期和生育能力低下。总体假设是同源结构域转录因子VAX 1是生育力所必需的，因为它在GnRH神经元和SCN成熟的发育过程中以及在成年期调节节律的重要性。目的1将研究VAX 1在发育过程中决定GnRH神经元命运的机制，并研究VAX 1在成熟GnRH神经元节律产生中的重要性。目的2将讨论VAX 1和SIX 3在SCN功能中的重要性，以及打乱的节律产生如何影响昼夜节律行为和生育能力。目的3研究SCN发育过程中同源结构域蛋白的级联反应，及其在SCN起搏功能中的作用。最终目标是确定心律异常的治疗靶点。我相信这些研究将为生育调节的新机制提供有价值的见解，并确定GnRH神经元和SCN中节律产生和生殖功能之间的关联。这种多方面、跨学科的方法应能全面了解VAX 1在成年期GnRH神经元成熟和功能中的重要性，以及SCN完全成熟和正确功能在生育中的意义。这是一个独立的理想途径，由一群杰出的导师，广泛的新颖培训，世界一流的科学环境和明确的部门承诺支持。

 DESCRIPTION (provided by applicant): 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.