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

基本信息

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
项目类别：
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

项目摘要

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，下丘脑中生长抑素（SST）表达的丧失与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（即那些支配脑干交感神经的）直接支配骨髓（BM）并且保护这个虽小但重要的种群似乎对于预防交感神经亢进。交感神经过度活跃导致 BM 功能障碍，增加促炎性单核细胞的产生和释放有助于发展糖尿病视网膜病变（DR）。 BM 功能障碍导致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自主神经的神经炎症效应神经元导致自主神经元兴奋的自动持续循环。这些研究得出的中心假设是恢复海温水平和糖尿病下丘脑的神经元活动达到非糖尿病水平将减少慢性脑干交感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和视网膜炎症导致博士。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下丘脑脑干自主效应核的过度兴奋和慢性过度激活 BM 导致 BM 病理学。在目标2中，我们将确定是否恢复SST 使用表达 SST 的载体可降低糖尿病啮齿动物下丘脑神经元的水平慢性过度激活 BM 交感神经元活动，预防/逆转 BM 功能障碍和预防/治疗 DR。在目标 3 中，我们将测试长期药理学是否有效。使用生长抑素类似物奥曲肽鼻内递送进行补充预防糖尿病引起的 BM 功能障碍和 DR，并阻止下丘脑炎症停止自主神经元兴奋的自动持续循环。 SST 类似物已在人体中进行了广泛测试，该策略可以立即转化为临床使用采用鼻内给予SST类似物来减少糖尿病引起的交感神经兴奋过度活跃是导致 BM 病理、全身炎症和 DR 的原因。