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.
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. Our proposal will examine an entirely novel mechanism for the development of DR: Autonomic nervous system (ANS) hyperactivity that impairs bone marrow function leading to generation of increased numbers of tissue infiltrating monocytes. We propose to target ANS brain regions, specifically the hypothalamus with a virus expressing somatostatin or with a somatostatin analogue that blocks ANS hyperactivity and downstream events to prevent/treat DR.
