Imaging Cell Signaling Events During Luteinizing Hormone Pulses

黄体生成激素脉冲期间的细胞信号传导事件成像

• 批准号: 7237598
• 负责人: Deborah A Roess
• 金额: $ 6.6万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7237598
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Amyloid; Biology of Aging; Brain; Cell Line; Cells; Characteristics; Clinical Research; Cyan Fluorescent Protein; Cyclic AMP; Cyclophosphamide/Fluorouracil/Prednisone; Development; Disease; Elevation; Enantone; Event; Exposure to; Fluorescence Resonance Energy Transfer; Frequencies; Funding Mechanisms; Gender; Goals; Gonadotropin Releasing Hormone Inhibitor; Hormone Receptor; Hormones; Human Chorionic Gonadotropin; Image; Incidence; Institutes; Integral Membrane Protein; LH Receptors; Life; Luteinizing Hormone; Mediating; Methods; Monitor; Mus; Nervous system structure; Neuroblastoma; Ovarian; Patients; Physiologic pulse; Postmenopause; Process; Protein Precursors; Protein Secretion; Proteins; Pulse taking; Research; Risk Factors; Signal Transduction; Technology; Time; Woman; age effect; aging population; base; cognitive function; fluorescence microscope; improved; men; programs; receptor function; response

DESCRIPTION (provided by applicant): Elevations of luteinizing hormone (LH) levels with aging have been implicated in the development of Alzheimer's Disease (AD); evidence from clinical studies suggests that treatment of patients with a GnRH antagonist, Lupron, reduces LH levels, slows the progression of AD and improves cognitive function. Although there have been studies implicating LH effects on processing of amyloid-¿ in the murine brain and M17 cells, there is surprisingly little known about direct effects of LH on the nervous system. Recent studies addressing this question have used fixed concentrations of LH and ignored the fact that LH secretion, particular in women, is strongly pulsatile and that there are effects of aging on the amplitude of LH pulses. Here we propose to examine the effects of high amplitude LH pulses on M17 cells, a neuroblastoma cell line which expresses LH receptors and processes amyloid-¿ from its precursor. LH receptor pulses characteristic of young women and of post-menopausal women will be compared. We hypothesize that exposure of M17 neuroblastoma cells to LH pulses at amplitudes characteristic of those in post-menopausal women significantly increases the secretion of amyloid-¿, a protein that appears in excess in the brains of patients with AD. These studies will also develop, for the first time, strategies for imaging events associated with LH-mediated signaling in living cells during exposure to hormone. We have chosen the R03 mechanism for this application for several reasons. This project involves the "development of new research technology", a goal of the NICHD's R03 funding mechanism. Support for this R03 application will permit a proof-of-principal demonstration of several biophysical approaches to monitor LH receptor function in real time. These approaches will be incorporated into an R01 application containing a detailed examination of signaling by ovarian cells in response to pre-ovulatory LH pulses and the LH surge. In addition, this project is of limited scope and likely to be completed within two years. Shared support for this project from the Biology of Aging Program (BAP) in the National Institute of Aging might also be appropriate. Changes in LH pulsatility with aging are implicated in the development of AD and thus represent an "adverse change" that may be a risk factor for development of a disease that occurs with high frequency in an aging population.

描述（由申请人提供）：随着年龄的增长，促性腺激素（LH）水平升高与阿尔茨海默病（AD）的发展有关;临床研究的证据表明，用GnRH拮抗剂Lupron治疗患者可降低LH水平，减缓AD的进展并改善认知功能。虽然已经有研究表明LH对小鼠大脑和M17细胞中淀粉样蛋白的加工有影响，但令人惊讶的是，关于LH对神经系统的直接影响知之甚少。最近解决这个问题的研究使用固定浓度的LH，忽略了LH分泌（特别是女性）是强烈脉动的，并且衰老对LH脉冲幅度有影响的事实。在这里，我们建议检查高振幅LH脉冲对M17细胞的影响，M17细胞是一种神经母细胞瘤细胞系，表达LH受体并从其前体加工淀粉样蛋白。将比较年轻女性和绝经后女性的LH受体脉冲特征。我们假设，M17神经母细胞瘤细胞暴露于绝经后妇女特有幅度的LH脉冲显著增加了淀粉样蛋白的分泌，淀粉样蛋白是一种在AD患者大脑中过量出现的蛋白质。这些研究还将首次开发与LH介导的活细胞中的信号传导相关的成像事件的策略。我们选择R 03机制用于此应用有几个原因。该项目涉及“开发新的研究技术”，这是NICHD R 03资助机制的一个目标。对R 03应用程序的支持将允许对几种生物物理方法进行验证，以真实的实时监测LH受体功能。这些方法将被纳入R 01申请，其中包含对卵巢细胞响应排卵前LH脉冲和LH峰的信号传导的详细检查。此外，该项目的范围有限，可能在两年内完成。国家老龄化研究所的老龄化生物学项目（BAP）对这个项目的共同支持也可能是合适的。LH脉动性随年龄的变化与AD的发展有关，因此代表了一种“不利变化”，可能是老年人群中发生频率较高的疾病发展的风险因素。