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

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

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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.

我们已经表明，下丘脑中生长抑素（SST）表达的丧失是与脑干交感自主效应器的慢性兴奋性激活相关糖尿病中的神经元。我们有证据表明下丘脑下丘脑SST神经元（即那些支配脑干交感神经）直接支配骨髓（BM）保存这个小但重要的人群似乎与防止交感性多动症。交感性多动症导致BM功能障碍，增加促炎单核细胞的产生和释放，有助于发展糖尿病性视网膜病（DR）。 BM功能障碍引起的全身性单核细胞增多也可用于促进下丘脑和脑干交感神经的神经炎症效应神经元导致自主神经元激发的自动过度周期。这些研究提出的中心假设是恢复SST水平和糖尿病下丘脑的神经元活性至非糖尿病水平将减少慢性脑干交感神经效应神经元的兴奋性激活，避免 BM病理学以及随后的全身性和视网膜炎症的发展导致博士。在AIM 1中，我们将确定SST神经元活动的丧失是否导致持久性脑干自主效应核和慢性激活的下丘脑高激发导致BM病理学的BM。在AIM 2中，我们将确定SST是否恢复在糖尿病啮齿动物下丘脑神经元中使用载体表达SST的水平将减少慢性化过交感神经元活性向BM的激活，预防/反向BM 功能障碍并预防/治疗DR。在AIM 3中，我们将测试长期药理学是否使用鼻内递送的生长抑素类似物（Octreotide）补充防止糖尿病引起的BM功能障碍和DR，并阻止下丘脑炎症以停止自主神经元激发的自动过度周期。 SST类似物已经在人类中进行了广泛的测试，该策略可以立即转化为临床用途采用鼻内施用SST类似物来减少糖尿病引起的交感神经负责BM病理学，全身性炎症和DR的多动症。