The role of Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons in the pathogenesis of polycystic ovarian syndrome

Kisspeptin/神经激肽 B/强啡肽 (KNDy) 神经元在多囊卵巢综合征发病机制中的作用

• 批准号: 10331567
• 负责人: Aleisha Moore
• 金额: $ 24.9万
• 依托单位: KENT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-04 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331567
• 关键词: Acute; Address; Adult; Affect; Afferent Neurons; Age; Androgens; Area; Basic Science; Brain; Cells; Clinical Research; Consequentialism; Contraceptive methods; Defect; Development; Disease; Dynorphins; Estradiol; Feedback; Fertility; Frequencies; Functional disorder; GNRH1 gene; Generations; Genetic; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Hormone secretion; Hyperandrogenism; Hypothalamic structure; Impairment; Infertility; Intervention; KISS1 gene; Knowledge; Lead; Location; Luteinizing Hormone; Maps; Mediating; Menstrual cycle; Mentors; Metabolic; Morphology; Mus; Neurokinin B; Neuronal Dysfunction; Neurons; Neurosciences; Optics; Ovarian; Ovarian Diseases; Ovary; Ovulation; Pathogenesis; Pathway interactions; Patients; Peptides; Phase; Phenotype; Physiologic pulse; Pituitary Gland; Polycystic Ovary Syndrome; Population; Prevention strategy; Production; Progesterone; Rabies; Regulation; Research; Role; Science; Steroids; Symptoms; Synapses; Syndrome; Techniques; Technology; Testing; Therapeutic; Three-dimensional analysis; Tissues; Training; Transgenic Mice; Viral; Woman; Work; career; hormonal signals; hormone sensitivity; mouse model; neural circuit; neuroendocrine phenotype; neuron loss; neuronal circuitry; new therapeutic target; optogenetics; peptide hormone; prenatal; prevent; receptor expression; reproductive; rimorphin; skills; steroid hormone; steroid hormone receptor; tool; young woman

Project Summary: Polycystic ovarian syndrome (PCOS) is the leading cause of infertility worldwide. The cardinal features of the syndrome are anovulatory and cystic ovaries, disrupted menstrual cycles and hyperandrogenism. The ovaries are controlled by a small group of neurons that reside in the hypothalamus, gonadotropin-releasing hormone (GnRH) neurons. Activity in these neurons regulate pulsatile luteinizing hormone (LH) release from the pituitary gland, which controls ovulation and sex steroid hormone production at the ovary. Steroid hormones, in turn, act in the brain through an afferent neuronal network to provide critical feedback to GnRH neurons. In many women with PCOS this feedback pathway is impaired, resulting in increased GnRH/LH pulse frequency which drives the downstream consequences of the syndrome. Neurons upstream from GnRH neurons that co-express the peptides Kisspeptin, Neurokinin B and Dynorphin (KNDy neurons) are heavily implicated in both steroid hormone feedback and GnRH/LH pulse generation, therefore, perturbations in the normal function of this population may manifest as the PCOS neuroendocrine phenotype. However, recent evidence indicates that steroid hormone signaling does not occur directly at the level of KNDy neurons, implicating impaired steroid hormone feedback occurs within a population upstream to KNDy neurons. As the identity of afferents to KNDy neurons is largely unknown, the long term goal of this research is to characterize the phenotype and functional roles of neuronal populations that regulate KNDy neuron activity, and, determine whether changes in the identified neurons contribute to the pathophysiology of PCOS. To achieve this, we will use a well characterized mouse model of PCOS induced by prenatal androgen treatment. The mentored phase of this proposal will include a sophisticated combination of transgenic mice, rabies-mediated tract tracing techniques, whole brain optical clearing and three-dimensional analysis to define the upstream KNDy neuronal populations and determine whether impaired GnRH/LH hypersecretion is the result of altered synaptic input to KNDy neurons (Aim 1) and/or altered activity of afferents to KNDy neurons (Aim 2). At the end of my mentored phase, I will have gained expertise in neuroanatomical techniques necessary for transitioning to independence in my field and trained in functional techniques required for the Independent phase of this proposal. In Aim 3, I will use chemogenetic and/or optogenetic tools to define whether changes in the regulation of KNDy neurons by afferent populations is sufficient to increase GnRH/LH pulsatile release. In Aim 4, I will use viral-mediated deletion techniques to confirm that impaired steroid hormone sensitivity in afferent neurons drives downstream changes and results in the PCOS phenotype of impaired steroid hormone feedback and resultant infertility. These studies have the potential to identify new components of the circuitry critical for the neuronal control of fertility, and may provide novel targets for the therapeutic treatment of PCOS in adulthood, or, to prevent the development of the disorder in young women.

多囊卵巢综合征（PCOS）是导致不孕的主要原因。的 该综合征的主要特征是无排卵和囊性卵巢，月经周期中断， 雄激素过多症卵巢由一小群位于下丘脑的神经元控制， 促性腺激素释放激素（GnRH）神经元。这些神经元的活动调节脉动黄体化 促性腺激素（LH）从脑垂体释放，控制排卵和性类固醇激素的产生， 卵巢反过来，类固醇激素通过传入神经元网络在大脑中起作用，以提供关键的 反馈给GnRH神经元。在许多患有PCOS的女性中，这种反馈途径受损，导致 促性腺激素释放激素/黄体生成素脉冲频率，其驱动综合征的下游后果。上游神经元 来自共表达肽Kisspeptin、神经激肽B和强啡肽的GnRH神经元（KNDy神经元）， 与类固醇激素反馈和GnRH/LH脉冲产生密切相关，因此， 该群体的正常功能可表现为PCOS神经内分泌表型。但最近的 证据表明类固醇激素信号传导不直接发生在KNDy神经元的水平， 暗示受损的类固醇激素反馈发生在KNDy神经元上游的群体内。为 KNDy神经元传入的身份在很大程度上是未知的，这项研究的长期目标是表征 调节KNDy神经元活性的神经元群体的表型和功能作用，并确定 所鉴定的神经元的变化是否有助于PCOS的病理生理学。为了实现这一目标，我们将 使用一个由产前雄激素治疗诱导的PCOS的良好表征的小鼠模型。指导阶段 这项建议的一个复杂的组合将包括转基因小鼠，狂犬病介导的道跟踪， 技术，全脑光学透明和三维分析，以确定上游KNDy神经元 人群，并确定受损的GnRH/LH分泌过多是否是突触输入改变的结果， KNDy神经元（Aim 1）和/或KNDy神经元传入活动的改变（Aim 2）。在我的指导结束时， 在这个阶段，我将获得向独立过渡所需的神经解剖学技术方面的专业知识 在我的领域，并在本提案的独立阶段所需的功能技术培训。在目标3中，我 将使用化学遗传学和/或光遗传学工具来确定是否通过改变KNDy神经元的调节来改变KNDy神经元。 传入群体足以增加GnRH/LH脉冲释放。在目标4中，我将使用病毒介导 删除技术，以确认传入神经元中受损的类固醇激素敏感性驱动下游 改变并导致类固醇激素反馈受损的PCOS表型和由此产生的不孕症。 这些研究有可能确定神经元控制的关键电路的新组件， 生育能力，并可能提供新的目标，为治疗性治疗多囊卵巢综合征在成年期，或，以防止 在年轻女性中的疾病发展。