The Role of Kisspeptin in Female Reproductive Aging

Kisspeptin 在女性生殖衰老中的作用

• 批准号: 7546723
• 负责人: Jodi Downs
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7546723
• 关键词: Address; Affect; Age; Aging; Animals; Anterolateral; Cell Nucleus; Cells; Circadian Rhythms; Data; Estradiol; Estrogen Receptors; Estrus; Event; Feedback; Female; Fiber; G Protein-Coupled Receptor 54; Gene Proteins; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Human; Hypothalamic structure; Infertility; KISS1 gene; Luteinizing Hormone; Mediating; Menopause; Neurons; Neuropeptides; Neurosecretory Systems; Nodal; Organum Vasculosum Laminae Terminalis; Periodicity; Play; Population; Production; Puberty; Rattus; Receptor Cell; Relative (related person); Role; Testing; Time; Variant; Woman; age effect; age related; day; density; medial preoptic nucleus; middle age; nerve supply; neurochemistry; organum vasculosum of the lamina terminalis; protein expression; receptor; reproductive; reproductive axis; reproductive neuroendocrinology; response; senescence; young adult; Address; Affect; Age; Aging; Animals; Anterolateral; Cell Nucleus; Cells; Circadian Rhythms; Data; Estradiol; Estrogen Receptors; Estrus; Event; Feedback; Female; Fiber; G Protein-Coupled Receptor 54; Gene Proteins; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Human; Hypothalamic structure; Infertility; KISS1 gene; Luteinizing Hormone; Mediating; Menopause; Neurons; Neuropeptides; Neurosecretory Systems; Nodal; Organum Vasculosum Laminae Terminalis; Periodicity; Play; Population; Production; Puberty; Rattus; Receptor Cell; Relative (related person); Role; Testing; Time; Variant; Woman; age effect; age related; day; density; medial preoptic nucleus; middle age; nerve supply; neurochemistry; organum vasculosum of the lamina terminalis; protein expression; receptor; reproductive; reproductive axis; reproductive neuroendocrinology; response; senescence; young adult

DESCRIPTION (provided by applicant): This proposal seeks to evaluate the role of KiSS-1 in the age-related changes in responsiveness of GnRH neurons to estradiol (E2) in the female rat. Although strong evidence indicates that KiSS-1 and GPR54 are critical for E2 feedback onto GnRH neurons in young adults across many species including humans, we have virtually no understanding of how this mechanism may change during the middle-age transition towards reproductive senescence. The following specific aims will address the hypothesis that a decline in responsiveness of KiSS-1 neurons to E2 plays a critical role in mediating the reduced magnitude and delay of the LH surge in aging female rats. Our first aim will be to determine the effect of age and time of day on KiSS-1. We will investigate whether the production of KiSS-1 and estrogen receptors (ERs) from KiSS-1 neurons, or KiSS-1 and ER cell density change with age in the AVPV. We will determine whether there is a diurnal variation in KiSS-1 gene and protein expression. Additionally we will examine the effect of age and time of day on KiSS-1 axonal density to GnRH neuronal populations critical for the LH surge. Our second aim will be to evaluate the KiSS-1 neuron response to E2 in the AVPV with age. We will accomplish this aim by testing the capacity of E2 to activate KiSS-1 neurons in the AVPV with age and by determining to what extent E2-induced KiSS-1 neuronal activation depends on time of day. Additionally, we will determine whether aging, E2, and time of day differentially affect GPR54 expression in the GnRH neuronal populations of the organum vasculosum of the lamina terminalis/rostral medial preoptic nucleus (OVLT/rMPN), a region known to be involved in generating the GnRH/LH surge. Our third, and final aim, will be to evaluate the effect of age and time of day on the capacity of KiSS-1 to mediate an E2-induced LH surge. In this aim it will be critical to assess whether KiSS-1, given centrally, will elicit a GnRH/LH surge in middle-aged rats and if time of day is a critical factor. Furthermore, we will determine whether age and time of day differentially affect the capacity of centrally administered KiSS-1 to activate GnRH neurons. It is possible that GnRH neurons of middle-aged animals will be less responsive to KiSS-1, so we will examine if GPR54 expression changes with age and time of day. Findings from the proposed study will have critical implications to the understanding of the neuroendocrine involvement of the onset of menopause and age-related infertility in women.

描述（由申请人提供）：该提案旨在评估KISS-1在雌性大鼠中GnRH神经元对雌二醇（E2）的响应性变化中的作用。尽管有力的证据表明，KISS-1和GPR54对于包括人类在内的许多物种的年轻人中的E2反馈对GNRH神经元的反馈至关重要，但我们几乎不了解这种机制在中年过渡期间向生殖衰老的过渡期间如何改变。以下具体目的将解决以下假设：kiss-1神经元对E2的反应能力下降在介导衰老的女性大鼠LH激增的幅度减少和延迟方面起着至关重要的作用。我们的第一个目的是确定一天中的年龄和时间对KISS-1的影响。我们将研究来自KISS-1神经元的KISS-1和雌激素受体（ER）的产生，还是AVPV年龄随着年龄的增长而变化的KISS-1和ER细胞密度。我们将确定KISS-1基因和蛋白质表达是否存在昼夜变化。此外，我们将研究年龄和时间的年龄对KISS-1轴突密度对LH激增至关重要的GNRH神经元种群的影响。我们的第二个目标是随着年龄的增长，在AVPV中评估对E2的KISS-1神经元反应。我们将通过测试E2的能力随着年龄的增长而激活AVPV中的KISS-1神经元的能力来实现这一目标，并确定E2诱导的KISS-1神经元激活的程度取决于一天中的时间。此外，我们将确定衰老，E2和一天中的时间是否会影响GPR54在GnRH神经元群体中的GPR54表达是否会影响层末端/延髓内侧前核（OVLT/RMPN）的细胞器脉管群，该区域已知与GNRH/lh emage一起产生GNRH/LH emage。我们的第三个也是最终目标是评估一天中的年龄和时间对KISS-1的能力介导E2引起的LH激增的影响。在此目标中，重要的是要评估KISS-1在中心地位是否会引起中年大鼠的GNRH/LH激增，以及一天中的时间是关键因素。此外，我们将确定一天中的年龄和时间是否会差异地影响中心施用的KISS-1激活GNRH神经元的能力。中年动物的GnRH神经元可能对KISS-1的反应较低，因此我们将检查GPR54表达是否随着一天的年龄和时间而变化。拟议研究的发现将对对女性更年期发作和与年龄相关的不育的神经内分泌受累的理解具有关键意义。