Glucosensing Neurons in Euglycemia, Hypoglycemia & HAAF

描述(由申请人提供)： 本研究旨在探讨反复低血糖对下丘脑腹内侧核(VMN)葡萄糖感觉神经元的影响。总体目标是更清楚地了解(A)血糖变化是如何转化为神经元信号的，以及(B)这些神经元信号是如何整合起来的，以启动对低血糖的反调节反应。该提案中的两个假设直接解决了这些问题。 假设I是VMN葡萄糖敏感神经元具有感觉即将到来的低血糖和启动反调节反应的信号的潜力。这一假说源于我们对VMN葡萄糖敏感神经元对细胞外葡萄糖生理相关变化的反应能力的了解。 假说II认为，VMN葡萄糖感觉神经元从大脑对葡萄糖稳态调节重要的区域接收信息并投射到这些区域。本文提出的第一组实验将定义生理上相关的VMN葡萄糖感觉神经元亚型对生理葡萄糖浓度的反应性。然后，我们将确定反复低血糖是否或如何改变这些反应，这些低血糖足以导致低血糖相关的自主神经功能衰竭。我们还将探索葡萄糖感应转导的细胞机制，以便了解任何反应性变化背后的机制。第二组实验将为理解VMN葡萄糖感觉神经元的潜在整合作用提供基础。这将通过识别来自其他葡萄糖感觉神经元的突触前输入和传递到VMN，以及识别VMN葡萄糖感觉神经元的下丘脑靶点来完成。 这些研究将提供有关大脑调节葡萄糖稳态的方式以及葡萄糖稳态的扰动改变这些中枢机制的方式的重要信息。这将促进针对I型糖尿病及其主要现代并发症低血糖的新的有效治疗方法的开发。

DESCRIPTION (provided by applicant): This proposal investigates the effects of recurrent hypoglycemia on glucose sensing neurons in the ventromedial hypothalamic nucleus (VMN). The overall objective is to gain a clearer understanding of (a) how changes in glucose are transduced into neuronal signals, and (b) how those neuronal signals are integrated to initiate the counterregulatory response to hypoglycemia. The two hypotheses in this proposal directly address these issues. HYPOTHESIS I is that VMN glucose sensing neurons have the potential to sense impending hypoglycemia and signal for the initiation of the counterregulatory response. This hypothesis derives from our knowledge of the ability of VMN glucose sensing neurons to respond to physiologically relevant changes in extracellular glucose. HYPOTHESIS II is that VMN glucose sensing neurons receive information from and project to brain regions important to the regulation of glucose homeostasis. The first set of experiments proposed herein will define the responsiveness of physiologically relevant subtypes of VMN glucose sensing neurons over physiological glucose concentrations. We will then determine whether or how the responses are altered by recurrent hypoglycemia sufficient to induce hypoglycemia associated autonomic failure. We will also explore the cellular mechanism of glucose sensing transduction so that the mechanisms that underlie any change in responsiveness can be understood. The second set of experiments will provide the basis for understanding the potential integrative role of VMN glucose sensing neurons. This will be accomplished by identifying presynaptic inputs and transmitters to the VMN from other glucose sensing neurons and identifying the hypothalamic targets of VMN glucose sensing neurons. These studies will provide important information regarding the way that the brain regulates glucose homeostasis and the way that perturbations in glucose homeostasis alter these central mechanisms. This will facilitate the development of new and effective treatments for Type I diabetes mellitus and its major modern complication hypoglycemia.