AGE RELATED CHANGES IN PITUITARY LACTOTROPHS

这项建议的具体目的是确定与年龄有关的 垂体前叶催乳素反应的改变。 的一大重点 本工作将对细胞信号转导机制， 乳营养素，特别是磷脂酰肌醇-4，5- 二磷酸盐（PIP2）。 这产生了肌醇磷酸的积累 (IPs)，特别是肌醇1，4，5-三磷酸（IP3），其用作 胞内第二信使 催乳素分泌和细胞内容物， 肌醇磷酸积累和磷脂代谢将是 在来源于以下动物的垂体前叶的原代培养物中测定： 3个不同年龄供体组，即年轻（3 - 4个月）、成熟（7 - 8个月 月龄）和老龄（22 - 24月龄）雄性和雌性Sprague-Dawley大鼠。 培养物将用促分泌素（TRH、血管紧张素II或 神经降压素），其已显示通过PIP2增加催乳素释放 水解 这些促分泌素的刺激活性，以及 将测定多巴胺抑制这些反应的能力。 在 为了区分受体结合的可能差异， 这些促分泌素的特性，受体将通过 给予佛波醇酯。 此外，参与 将测定雌激素对垂体反应性的影响。 这很好 以两种不同的方式完成。 首先，一些雌性大鼠将 在3 - 4个月时切除卵巢，并作为单独的垂体组纳入 每个老年组（即成年组和老年组）的供体。 二是 雌激素对垂体的直接影响将通过添加 到文化。 将对所有供体组中的催乳素数量进行定量 所有细胞将在无类固醇培养基中孵育。 衰老使许多生理功能发生变化。 内分泌系统发生重大变化，包括 垂体前叶分泌功能，最值得注意的是， 催乳素分泌 老龄化也明显与增加 垂体腺瘤（涉及催乳素人群）。 因此，在本发明中， 垂体前叶催乳素反应性的改变可能 是垂体腺瘤的早期标志 重要的是要了解 与老化过程相关的特征和机制， 正常衰老和衰老发病机制之间的关系 可以确定相关疾病，特别是考虑到 今年人口结构日益向老年人口转变 国家

The specific aim of this proposal is to characterize age-related alterations in anterior pituitary lactotroph responses. A major focus of this work will be on the cell signal transduction mechanism of the lactotroph, specifically the hydrolysis of phosphatidyl-inositol-4,5- bisphosphate (PIP2). This produces an accumulation in inositol phosphates (IPs), notably inositol 1,4,5-triphosphate (IP3) which serves as an intracellular second messenger. Prolactin secretion and cell content, inositol phosphate accumulation and phospholipid metabolism will be determined in primary cultures derived from anterior pituitary glands from three different aged donor groups, i.e. young (3-4 months), mature (7-8 months) and old (22-24 months) male and female Sprague-Dawley rats. Cultures will be treated with secretagogues (TRH, Angiotensin II or neurotensin) which have been shown to increase prolactin release via PIP2 hydrolysis. The stimulatory activity of these secretagogues, as well as the ability of dopamine to inhibit these responses will be determined. In order to distinguish between possible differences in receptor binding characteristics of these secretagogues, the receptors will be by passed by administration of phorbol esters. The addition, the involvement of estrogen on pituitary responsiveness will be determined. This well be accomplished in two different ways. First, a number of female rats will be ovariectomized at 3-4 months and included as a separate group of pituitary donors for each of the older groups (i.e. mature and old). Second, the direct effects of estrogen on the pituitary will be assessed by adding it to the cultures. Lactotroph number will be quantified in all donor groups and all cells will be incubated in steroid free media. Aging produces a number of alterations in many physiologic functions. Significant changes occur in the endocrine system, including alterations in anterior pituitary secretory function, most notable, an increase in prolactin secretion. Aging is also clearly associated with an increase in pituitary adenomas (which involves the lactotroph population). Thus, alterations in the responsiveness of the anterior pituitary lactotroph may be an early marker of pituitary adenomas. It is important to understand the characteristic(s) and mechanism(s) associated with the aging process so that the relationship between normal aging and the pathogenesis of age- related diseases can be determined, especially taking into consideration the growing shift in demographics toward the elderly population in this country.