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

基本信息

批准号：
10366065
负责人：
Aleisha Moore
金额：
$ 20.85万
依托单位：
KENT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10366065
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

项目摘要

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.

项目摘要：多囊卵巢综合症（PCOS）是全世界不孕的主要原因。这该综合征的主要特征是卵巢无排卵和囊性、月经周期紊乱和雄激素过多症。卵巢由位于下丘脑的一小群神经元控制，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垂体释放激素 (LH)，控制排卵和性类固醇激素的产生卵巢。类固醇激素反过来通过传入神经元网络在大脑中发挥作用，提供关键的反馈给 GnRH 神经元。在许多患有 PCOS 的女性中，这种反馈途径受到损害，导致 GnRH/LH 脉冲频率驱动该综合征的下游后果。上游神经元来自共表达肽 Kisspeptin、神经激肽 B 和强啡肽（KNDy 神经元）的 GnRH 神经元与类固醇激素反馈和 GnRH/LH 脉冲产生密切相关，因此，扰动该人群的正常功能可能表现为PCOS神经内分泌表型。然而，最近有证据表明类固醇激素信号传导并不直接发生在 KNDy 神经元水平，这表明类固醇激素反馈受损发生在 KNDy 神经元上游的群体中。作为 KNDy 神经元传入的身份很大程度上未知，本研究的长期目标是表征调节 KNDy 神经元活动的神经元群的表型和功能作用，并确定所识别的神经元的变化是否有助于多囊卵巢综合征的病理生理学。为了实现这一目标，我们将使用经过产前雄激素治疗诱导的特征明确的 PCOS 小鼠模型。指导阶段该提案将包括转基因小鼠、狂犬病介导的肠道追踪的复杂组合技术、全脑光学清除和三维分析来定义上游 KNDy 神经元人群并确定 GnRH/LH 分泌过多是否是突触输入改变的结果 KNDy 神经元（目标 1）和/或改变 KNDy 神经元的传入活动（目标 2）。在我的指导结束时阶段，我将获得过渡到独立所需的神经解剖学技术方面的专业知识在我的领域，并接受了本提案独立阶段所需的功能技术方面的培训。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 KNDy 神经元的调节是否发生变化传入群体足以增加 GnRH/LH 脉冲释放。在目标 4 中，我将使用病毒介导的删除技术确认传入神经元驱动下游类固醇激素敏感性受损类固醇激素反馈受损的 PCOS 表型的变化和结果以及由此导致的不孕症。这些研究有可能识别出对神经元控制至关重要的电路的新组件。生育能力，并可能为成年期 PCOS 的治疗提供新的靶点，或者预防年轻女性中该疾病的发展。