Neuroprotection in the Aging Female Brain

描述（由申请人提供）：在女性中，绝经期内分泌环境的破坏增加了中风和神经炎症性疾病的风险。使用无循环雌性大鼠来模拟绝经后状态，我们的研究表明，与成熟（循环）成年雌性相比，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的成年雌性具有保护作用，但矛盾的是，它会增加老年无环雌性的组织损伤。这些数据与WHI的研究一致，即接受激素治疗的老年妇女中风的风险升高，并强调了对这一群体需要新的治疗方法。基于我们最近的研究，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，IGF-1是一种神经保护肽激素，而IGF-1的年龄相关性下降几乎发生在所有物种中，破坏了雌激素的神经保护作用。我们的研究支持了这一假设，因为(1)中年（生殖衰老）雌性大鼠的IGF-1水平降低，(2)在中风模型中，向老年雌性大鼠输注IGF-1克服了雌激素在该组中的神经毒性作用。在这里，我们将研究雌激素和IGF-1在卒中恢复和梗死体积中的协同相互作用，以及这种相互作用在生殖衰老中改变的程度。其次，我们将研究雌激素/IGF-1在生殖衰老女性中风后改善星形细胞功能的程度。星形胶质细胞对IGF-1和雌激素均有反应，并在缺血环境的解毒中发挥重要作用。最后，我们将确定是否可以通过操纵IGF-1的表观遗传调节因子即microRNA来改善老年女性的中风结果。MiRNA是一种小型非编码RNA，调节大型基因网络，在细胞衰老、增殖（癌症）和损伤（中风）中发挥核心作用。具体来说，我们将识别和操纵调节IGF-1的miRNA，以改善老年女性中风的恢复。总的来说，这些研究将提供对雌激素的年龄划定的神经保护作用的理解，并为针对老年女性的中风治疗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. PUBLIC HEALTH RELEVANCE: Women are at a greater risk for stroke than men after menopause and estrogen therapy to this group unfortunately increases the risk and severity of this disease. In this application we will use an animal model of acyclic older female rats to develop a new therapeutic approach for stroke recovery that involves increasing the availability of a small protein IGF-1, either by directly infusing this peptide or via a class of bio-molecules called microRNA that regulate IGF-1.