Somatostatin blockade of CNS autonomic hyperactivity for treatment of diabetic retinopathy

生长抑素阻断中枢神经系统自主神经亢进治疗糖尿病视网膜病变

• 批准号: 9403831
• 负责人: Michael Edwin Boulton
• 金额: $ 50.19万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403831
• 关键词: Adopted; Autonomic Nerve Block; Autonomic nervous system; Biological Preservation; Blood - brain barrier anatomy; Blood Circulation; Bone Development; Bone Marrow; Brain Stem; Brain region; Cell Nucleus; Chronic; Clinical; Data; Development; Diabetes Mellitus; Diabetes prevention; Diabetic Angiopathies; Diabetic Retinopathy; Diphtheria Toxin; Event; Exhibits; Functional disorder; Gene Transfer; Generations; Genes; Human; Hyperactive behavior; Hypothalamic structure; Impairment; Individual; Inflammation; Injectable; Intranasal Administration; Lead; Mediating; Microvascular Dysfunction; Modeling; Monocytosis; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Octreotide; Pathology; Peripheral; Pharmacology; Population; Proteins; Publishing; Rattus; Regulation; Reporter; Retinal; Rodent; Rodent Model; Scheme; Somatostatin; Supplementation; Testing; Therapeutic Effect; Tissues; Translating; Validation; Virus; clinically relevant; designer receptors exclusively activated by designer drugs; diabetic; gene therapy; in vivo; monocyte; neuroinflammation; non-diabetic; novel; predictive modeling; prevent; restoration; selective expression; somatostatin analog; vector

We have shown that loss of somatostatin (SST) expression in the hypothalamus is associated with chronic excitatory activation of brainstem sympathetic autonomic effector neurons in diabetes. We have evidence that periventricular hypothalamic SST neurons (i.e. those that innervate brainstem sympathetics) directly innervate bone marrow (BM) and that preservation of this small, but important population appears to be particularly relevant to prevent sympathetic hyperactivity. Sympathetic hyperactivity leads to BM dysfunction with an increase in the generation and release of proinflammatory monocytes that contribute to the development of diabetic retinopathy (DR). Systemic monocytosis resulting from BM dysfunction also serves to promote neuroinflammation of the hypothalamus and of brainstem sympathetic autonomic effector neurons resulting in an auto-perpetuating cycle of excitation of autonomic neurons. The central hypothesis emerging from these studies is that restoring SST levels and neuronal activity in the diabetic hypothalamus to nondiabetic levels will reduce chronic excitatory activation of brainstem sympathetic autonomic effector neurons, avoid development of BM pathology and the subsequent systemic and retinal inflammation leading to DR. In Aim 1, we will determine whether loss of SST neuronal activity results in persistent hypothalamic hyper excitation of brainstem autonomic effector nuclei and chronic over activation of the BM leading to BM pathology. In Aim 2, we will determine whether restoration of SST levels using vector expressing SST in hypothalamic neurons of diabetic rodents will reduce chronic over activation of sympathetic neuronal activity to the BM, prevent/reverse BM dysfunction and prevent/treat DR. In Aim 3, we will test whether long-term pharmacological supplementation using intranasal delivery of the somatostatin analogue, octreotide, would prevent diabetes-induced BM dysfunction and DR, and block hypothalamic inflammation to stop the auto-perpetuating cycle of excitation of autonomic neurons. SST analogues have been tested extensively in humans and this strategy could be immediately translated to clinical use by adopting intranasal administration of SST analogues to reduce diabetes-induced sympathetic hyperactivity responsible for BM pathology, systemic inflammation and DR.

我们已经证明，下丘脑生长抑素（SST）表达的缺失， 与脑干交感神经自主效应器的慢性兴奋性激活有关 糖尿病中的神经元我们有证据表明，室周下丘脑SST神经元（即， 神经支配脑干交感神经的那些）直接神经支配骨髓（BM）， 保护这一小部分，但重要的人口似乎特别相关，以防止 交感神经过度活跃交感神经功能亢进导致BM功能障碍， 促炎性单核细胞的产生和释放，有助于 糖尿病视网膜病变（DR）。由BM功能障碍引起的系统性单核细胞增多症也有助于 促进下丘脑和脑干交感神经自主神经的神经炎症 效应神经元导致自主神经元的兴奋的自动持续循环。 这些研究提出的核心假设是， 糖尿病患者下丘脑的神经元活动降低到非糖尿病水平将减少慢性 脑干交感神经自主效应神经元的兴奋性激活，避免 BM病理学的发展以及随后的全身性和视网膜炎症 导致DR。 在目标1中，我们将确定SST神经元活动的丧失是否会导致持续性的 下丘脑脑干自主神经效应核团的过度兴奋和慢性过度激活 导致BM病理学。在目标2中，我们将确定是否恢复SST 在糖尿病啮齿动物的下丘脑神经元中使用表达SST的载体的水平将降低 慢性过度激活交感神经元对BM的活动，预防/逆转BM 在目标3中，我们将测试是否长期药理学 使用鼻内递送生长抑素类似物奥曲肽的补充将 预防糖尿病引起的BM功能障碍和DR，并阻断下丘脑炎症停止 自主神经元兴奋的自动持续循环。SST类似物已被 在人类中进行了广泛的测试，这种策略可以立即转化为临床应用， 采用SST类似物鼻内给药降低糖尿病诱导的交感神经 引起BM病理学、全身性炎症和DR的活动过度。