Hypothalamic control of reproductive aging

下丘脑控制生殖衰老

• 批准号: 7569313
• 负责人: ANDREA C GORE
• 金额: $ 27.52万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569313
• 关键词: Abbreviations; Affect; Age; Aging; Aging-Related Process; Agonist; Anabolism; Androgen Receptor; Animals; Area; Aspartate; Cell Nucleus; Cells; Clinical; Competence; Complex; Diestrus; Electron Microscopy; Estrogen Receptors; Estrous Cycle; Female; Follicle Stimulating Hormone; Gene Expression; Glutamates; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Hormonal; Hypothalamic structure; Laboratories; Life; Link; Longevity; Luteinizing Hormone; Medial; Mediating; Menopausal Symptom; Modeling; N-Methyl-D-Aspartate Receptors; NR1 gene; Neurons; Neurosecretory Systems; Neurotransmitters; Ovarian; Ovary; Perikaryon; Perimenopause; Pituitary Gland; Play; Post-Menopausal Hormone Replacement Therapy; Preoptic Areas; RNase protection assay; Rattus; Rodent; Role; Site; Sprague-Dawley Rats; System; Testing; Woman; age related; base; child bearing; gonad function; healthy aging; hypothalamic pituitary gonadal axis; improved; insight; medial preoptic nucleus; median eminence; middle age; reproductive; reproductive function; research study; senescence

DESCRIPTION (provided by applicant): It is becoming increasingly clear that the mechanisms for reproductive aging involve a complex interaction of the three levels of the hypothalamic-pituitary-gonadal (HPG) axis. In rats and other rodents, reproductive cycles become irregular at middle age and acyclicity ensues shortly thereafter, although the ovaries still contain functional follicles. These observations support the role of the hypothalamus and/or pituitary in the transition to acyclicity. My laboratory has been studying a role in reproductive senescence for GnRH neurons, the primary cells controlling reproductive function. Recent evidence suggests that a major mechanism for compromised HPG function during aging is due to age-related alterations in regulatory inputs to GnRH cells. Here, I will investigate the neuroendocrine mechanisms that underlie the transition to acyclicity at middle age, focusing on how the NMDA receptor (NMDAR), which mediates effects of the neurotransmitter glutamate, interacts with GnRH cells at their perikarya in the preoptic area (POA) and neuroterminals in the median eminence (ME), and the consequences of these effects on reproductive decline. My model is young (regular estrous cycles) and middle-aged (regular or irregular cycles, or acyclic) Sprague-Dawley rats; therefore, my analyses will take both age (young vs. middle-aged) and reproductive status (cyclic, irregularly cycling, or acyclic) into consideration as independent variables. Three Specific Aims are proposed to test our hypotheses. Aim 1 will investigate effects of age-related changes in NMDARs in POA, on GnRH cells specifically and in POA nuclei in general. Aim 2 will examine similar relationships in the ME. Aim 3 will study how NMDARs and estrogen receptors (ERs) may be expressed in the same target cells in POA and ME, including GnRH cells, and how these change during reproductive aging. Together, these studies will link GnRH neurons, NMDARs, and ERs, to elucidate how these systems act coordinately to result in the transition to acyclicity at middle age, and to provide insight into their mechanisms. My three Specific Aims form the basis for a model of the perimenopausal transition in women, an area relevant to improving healthy aging, and will provide fundamental and functional insights into the role of the hypothalamus in reproductive senescence. These experiments have clinical implications for postmenopausal hormone replacement therapy, for identifying non- hormonal approaches to treating menopausal symptoms, and for potentially expanding the reproductive lifespan, which is becoming more important as women continue to postpone childbearing until later in life.

描述（由申请人提供）：越来越清楚的是，生殖衰老的机制涉及下丘脑 - 垂体 - 基达尔（HPG）轴的三个水平的复杂相互作用。在大鼠和其他啮齿动物中，繁殖周期在中年不规则，随后不久随之而来，尽管卵巢仍然包含功能性卵泡。这些观察结果支持下丘脑和/或垂体在过渡到无环的作用。我的实验室一直在研究控制生殖功能的主要细胞GnRH神经元的生殖衰老中的作用。最近的证据表明，衰老期间HPG功能受损的主要机制是由于年龄相关的GNRH细胞的调节输入改变引起的。 Here, I will investigate the neuroendocrine mechanisms that underlie the transition to acyclicity at middle age, focusing on how the NMDA receptor (NMDAR), which mediates effects of the neurotransmitter glutamate, interacts with GnRH cells at their perikarya in the preoptic area (POA) and neuroterminals in the median eminence (ME), and the consequences of these effects关于生殖下降。我的模型是年轻的（常规的发情周期）和中年（常规或不规则的周期，或无性循环）Sprague-Dawley大鼠；因此，我的分析将同时考虑年龄（年轻人与中年）和生殖状态（环状，不规则循环或无性循环）作为自变量。提出了三个特定目标来检验我们的假设。 AIM 1将研究POA中NMDAR与年龄相关的变化对GNRH细胞和POA核的影响。 AIM 2将检查ME中的类似关系。 AIM 3将研究NMDAR和雌激素受体（ER）如何在POA和ME的同一靶细胞中表达，包括GNRH细胞，以及这些在生殖衰老期间如何变化。这些研究将共同​​将GNRH神经元，NMDAR和ERS连接起来，以阐明这些系统如何协同起作用，从而导致中年的过渡到无效性，并提供对其机制的见识。我的三个特定目的构成了女性围绝经期转变模型的基础，该领域与改善健康衰老有关，并将为下丘脑在生殖衰老中的作用提供基本和功能的见解。这些实验对绝经后激素替代疗法具有临床意义，用于鉴定非荷尔蒙治疗绝经症状的非激素方法，并有潜在地扩大生殖寿命，因为女性继续将妇女继续推迟到生命后期，这变得越来越重要。