Regulation of Retinal Cell Death in Diabetes

摘要 这项提案的总体目标是了解糖尿病如何损害视网膜的存活率 神经元。研究的具体目标是研究糖尿病如何引起高血糖和炎症。 中介物通过减少神经营养因子介导的信号通路加速视网膜神经元的死亡。 这一提议的基本原理是，理解危及人类生存的机制 视网膜神经元将带来预防糖尿病和其他视网膜患者视力丧失的改进方法 堕落的人。 糖尿病通过多种方式损害视网膜，包括高血糖、炎症和改变。 支持生存的信号，但导致神经元死亡的机制仍然不确定。生长因子 通过Akt(蛋白激酶B)的信号是神经元生存的中心，并且作为一个共享的 糖尿病、全身感染、免疫介导性炎症和退行性脑部疾病的特征。 许多临床和动物研究现已证实糖尿病引起的视网膜神经元死亡是一种 早期糖尿病视网膜病变的组成部分。研究人员已经证明，视网膜支持生存 通过胰岛素受体和Akt的信号通常被胰岛素、胰岛素样生长因子和 光和糖尿病降低了这种基础的促生存活动，伴随着视网膜神经元的开始 死亡。我们已经证明，高血糖干扰了培养的视网膜神经元的存活，现在发现 细胞因子阻断了生长因子的神经营养作用。根皮苷的降糖作用 治疗可减少糖尿病大鼠视网膜神经元的死亡，并恢复有利于生存的信号。 此外，眼部输送生长因子也增强了促生存信号，减少了视网膜细胞。 死亡。我们还建立了一种新的小鼠视网膜胰岛素受体条件性敲除模型 这为研究视网膜促生存信号的作用提供了一个强有力的工具。总而言之，这些数据 证明胰岛素受体/Akt信号是视网膜神经元的关键生存途径。因此，我们 提出高血糖和炎症损害神经营养因子介导的一般假设 糖尿病患者视网膜神经元的存活。利用生物化学、分子和遗传学的三个特定目标 视网膜神经元培养、糖尿病大鼠和胰岛素受体/Akt基因敲除小鼠的研究方法 帕奇将检验这一假说。一个强大的跨学科研究团队将阐明这些机制 高血糖和细胞因子通过损害神经营养因子介导的视网膜神经元在培养中的存活 系统和糖尿病大鼠体内。我们还将确定胰岛素受体/Akt信号对视网膜的影响 利用新型转基因小鼠研究糖尿病患者的神经元存活和视力。

Abstract The overall goal of this proposal is to understand how diabetes impairs the survival of retinal neurons. The specific objective is to investigate how diabetes-induced hyperglycemia and inflammatory mediators accelerate the death of retinal neurons by reducing neurotrophin-mediated signaling pathways. The rationale for this proposal is that understanding the mechanisms that compromise the survival of retinal neurons will lead to improved means to prevent vision loss in diabetes and other retinal degenerations. Diabetes damages the retina by multiple insults, including hyperglycemia, inflammation and altered pro-survival signaling, but the mechanisms that cause neurons to die remain uncertain. Growth factor signaling through Akt (protein kinase B) is central to the survival of neurons, and is impaired as a shared feature of diabetes, systemic infections, immune-mediated inflammation, and degenerative brain diseases. Numerous clinical and animal studies have now established diabetes-induced death of retinal neurons as a component of early diabetic retinopathy. The investigators have demonstrated that retinal pro-survival signaling via the insulin receptor and Akt is normally activated by insulin, insulin-like growth factors and light, and diabetes reduces this basal pro-survival activity concomitant with the onset of retinal neurons death. We have shown that hyperglycemia disrupts the survival of retinal neurons in culture and now find that cytokines block the neurotrophic actions of growth factors. Reduction of hyperglycemia with phlorizin treatment reduces the death of retinal neurons and restores pro-survival signaling in diabetic rats. Moreover, ocular delivery of growth factors also augments pro-survival signaling and reduces retinal cell death. We have also generated a novel mouse model with conditional retinal insulin receptor knockdown that provides a powerful tool to examine the role of retinal pro-survival signaling. Together, these data demonstrate that insulin receptor/Akt signaling is a key survival pathway for retinal neurons. Thus, we propose the general hypothesis that hyperglycemia and inflammation impair neurotrophin-mediated survival of retinal neurons in diabetes. Three specific aims using biochemical, molecular and genetic approaches in retinal neuron cultures, diabetic rats, and mice with knockdown of the insulin receptor/Akt pathway will test the hypothesis. A strong interdisciplinary research team of will elucidate the mechanisms by which hyperglycemia and cytokines impair neurotrophin-mediated survival of retinal neurons in a culture system and in diabetic rats. We will also determine the impact of insulin receptor/Akt signaling on retinal neuron survival and vision in diabetes using novel genetically modified mice.