Neuroprotection in the Aging Female Brain

描述(申请人提供)：在女性中，绝经期间内分泌环境的破坏会放大中风和神经炎性疾病的风险。使用非周期性雌性大鼠来模拟绝经后状态，我们的研究表明，与成熟(周期性)成年雌性大鼠相比，这些动物在实验性缺血性中风后遭受更大的组织损伤。此外，虽然雌激素治疗对成熟成年女性具有保护作用，但它却矛盾地增加了老年非周期女性的组织损伤。这些数据与WHI的研究一致，在接受激素治疗的老年女性中，中风的风险增加，并强调了为这一群体寻找新的治疗方法的必要性。根据我们最近的研究，我们假设雌激素的神经保护作用需要胰岛素样生长因子(IGF)-1的协同作用，胰岛素样生长因子-1是一种神经保护性多肽激素，几乎在所有物种中都会发生与年龄相关的IGF-1下降，从而破坏雌激素的神经保护作用。这一假设得到了我们的研究的支持，因为(1)IGF-1水平在中年(生殖衰老)雌性大鼠中降低，(2)在中风模型中，向老年雌性大鼠注射IGF-1克服了这一组中雌激素的神经毒性效应。在这里，我们将研究雌激素和IGF-1在卒中恢复和脑梗塞体积上的协同作用，以及这种作用在生殖衰老中的改变程度。其次，我们将检查雌激素/IGF-1在多大程度上可以改善生殖衰老女性中风后星形胶质细胞的功能。星形胶质细胞对IGF-1和雌激素都有反应，并在缺血环境的解毒中发挥关键作用。最后，我们将确定是否可以通过操纵IGF-1的表观遗传调节器，即microRNA来改善老年女性的中风结果。MiRNA是一种小的非编码RNA，调节大的基因网络，在细胞衰老、增殖(癌症)和损伤(中风)中发挥核心作用。具体地说，我们将识别和操纵调节IGF-1的miRNA，以改善老年女性中风的康复。总而言之，这些研究将提供对雌激素年龄限定的神经保护作用的理解，并为为老年女性量身定做的中风疗法的临床前研究奠定基础。

DESCRIPTION (provided by applicant): In women, the disruption of the endocrine environment during menopause amplifies the risk for stroke and neuro-inflammatory disease. Using acyclic female rats to model the postmenopausal state, our studies indicate that these animals sustain greater tissue damage following experimental ischemic stroke as compared to mature (cyclic) adult females. Furthermore, while estrogen treatment is protective to mature adult females, it paradoxically increases tissue damage in older acyclic females. These data are congruent with the WHI study, where the risk for stroke was elevated in older women receiving hormone therapy, and underscores the need for novel therapeutic approaches for this group. Based on our recent studies, we hypothesize that estrogens neuroprotective actions require the cooperative action of insulin-like growth factor (IGF)-1, a neuroprotective peptide hormone, and that age-related decline in IGF-1, which occurs in virtually all species, destabilizes the neuroprotective actions of estrogen. This hypothesis is supported by our studies in that (1) IGF-1 levels are reduced in the middle aged (reproductive senescent) female rat, and (2) in a stroke model, IGF-1 infusion to older females overcomes the neurotoxic effects of estrogen in this group. Here we will examine the cooperative interaction of estrogen and IGF-1 on stroke recovery and infarct volume and the extent to which this interaction is altered in reproductive senescence. Secondly, we will examine the extent that estrogen/IGF-1 can improve astrocyte function post stroke in reproductive senescent females. Astrocytes are responsive to both IGF-1 and estrogen and play a crucial role in detoxification of the ischemic environment. Finally we will determine if stroke outcomes can be improved in older females by manipulating epigenetic regulators of IGF-1 namely, microRNA. MiRNA, a type of small non-coding RNA, regulate large gene networks, and play a central role in cell senescence, proliferation (cancer) and injury (stroke). Specifically, we will identify and manipulate miRNA that regulate IGF-1 to improve stroke recovery on older females. Collectively these studies will provide an understanding of estrogen's age-delimited neuroprotective effects and form the foundation for pre-clinical studies of stroke therapy tailored to older females.