Compensatory Regulation of Energy Balance by Neurogenesis in Adult Hypothalamus

成人下丘脑神经发生对能量平衡的代偿性调节

基本信息

批准号：
8661761
负责人：
Allison W Xu
金额：
$ 31.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8661761
关键词：
Ablation Adult Affect Alzheimer&apos s Disease Body Weight Brain Brain Injuries Brain region Cell Proliferation Cell Proliferation Regulation Cell Transplantation Cell Transplants Cells Chronic Chronic Disease Ciliary Neurotrophic Factor Diabetes Mellitus Diabetic mouse Diphtheria Toxin Disease model Embryo Environment Evaluation Exhibits Genetic Homeostasis Hormones Human Huntington Disease Hypothalamic structure In Vitro Inhibition of Cell Proliferation Maintenance Mediating Metabolic Methods Mitotic Activity Mus Mutant Strains Mice Natural regeneration Nerve Degeneration Neurons Neuropeptides Obese Mice Obesity Patients Peripheral Physiological Property Protocols documentation Regulation Rodent Rodent Model Role Stem cell transplant Stem cells Stimulus Synapses Testing Therapeutic Transplantation adult neurogenesis blood glucose regulation brain volume cell killing cell type coping energy balance feeding genetic manipulation insight mutant nerve stem cell nestin protein neurogenesis neuron loss neurotrophic factor novel obesity treatment permissiveness repaired response spatiotemporal

项目摘要

DESCRIPTION (provided by applicant): Maintenance of energy balance in an ever-changing environment requires the brain to cope with a variety of genetic and physiologic insults. Compensatory regulation of energy balance is frequently observed but its underlying mechanisms remain largely unknown. We have recently shown that hypothalamic neurons important for energy balance regulation can be regenerated in adult hypothalamus in response to progressive degeneration of orexigenic AgRP/NPY neurons, and that inhibition of cell proliferation in the mutant brain affects feeding and adiposity. Our results suggest that regulation of cell proliferation in the adult hypothalamus could serve as a compensatory mechanism to maintain hypothalamic feeding functions. To date, the functional role of adult neurogenesis in energy balance regulation remains largely unexplored. Hypothalamus is generally considered non-neurogenic in the adulthood although abundant neural progenitor cells are present. However, neurodegeneration has been shown to be a potent stimulus of neurogenesis in normally non-neurgenic regions of the brain in both rodents and humans. In this proposal, we will test the hypothesis that modulation of cell proliferation in the adult hypothalamus serves as a repair mechanism to limit the extent of energy imbalance under pathophysiologic conditions. Specifically, we will examine the spatiotemporal activation of neural progenitor cells in the adult hypothalamus in response to degeneration of specific hypothalamic neurons. We will determine whether adult born hypothalamic neurons can respond appropriately to alteration of energy balance status and peripheral metabolic hormones. We will examine survival and projection outgrowth of these adult born neurons and their synaptic connectivity. In addition, we will evaluate hypothalamic neurogenic activity during chronic obesity and diabetes, conditions that are associated with decreased brain volume and neuronal cell death in rodents and humans. By using a temporally inducible and cell type specific cell ablation approach, we will determine the functional significance of adult neural progenitors in compensatory regulation of energy balance under normal, obese and diabetes conditions. Finally, We will investigate neurogenic activity of transplanted neural progenitor cells in adult hypothalamus, and explore therapeutic potential of neural progenitor cell transplantation in treatment of obesity caused by neurodegeneration of hypothalamic neurons. Together, our study will provide critical information on the role of neurogenesis in compensatory regulation of energy balance. It will provide novel insight into therapeutic potential of neural stem cells in treatment of hypothalamic neurodegeneration that are associated with a variety of chronic diseases and brain injuries.

描述（由申请人提供）：在不断变化的环境中维持能量平衡需要大脑应对各种遗传和生理损伤。能量平衡的补偿性调节经常被观察到，但其潜在机制仍然很大程度上未知。我们最近发现，对于能量平衡调节很重要的下丘脑神经元可以在成年下丘脑中再生，以响应食欲 AgRP/NPY 神经元的进行性退化，并且抑制突变大脑中的细胞增殖会影响进食和肥胖。我们的结果表明，成人下丘脑细胞增殖的调节可以作为维持下丘脑摄食功能的补偿机制。迄今为止，成人神经发生在能量平衡调节中的功能作用在很大程度上仍未被探索。尽管存在丰富的神经祖细胞，但下丘脑在成年后通常被认为是非神经源性的。然而，神经变性已被证明是啮齿动物和人类大脑正常非神经源性区域神经发生的有效刺激。在本提案中，我们将测试以下假设：成人下丘脑细胞增殖的调节可作为一种修复机制，以限制病理生理条件下能量失衡的程度。具体来说，我们将检查成人下丘脑中神经祖细胞响应特定下丘脑神经元变性的时空激活。我们将确定成年下丘脑神经元是否能够对能量平衡状态和外周代谢激素的改变做出适当的反应。我们将检查这些成年神经元的存活和投射生长及其突触连接。此外，我们还将评估慢性肥胖和糖尿病期间下丘脑的神经源性活动，这些疾病与啮齿动物和人类的脑容量减少和神经元细胞死亡有关。通过使用时间诱导和细胞类型特异性细胞消融方法，我们将确定成人神经祖细胞在正常、肥胖和糖尿病条件下能量平衡代偿调节中的功能意义。最后，我们将研究移植的神经祖细胞在成人下丘脑中的神经活性，并探索神经祖细胞移植治疗下丘脑神经元神经变性引起的肥胖的治疗潜力。总之，我们的研究将提供有关神经发生在能量平衡补偿性调节中的作用的关键信息。它将为神经干细胞治疗与多种慢性疾病和脑损伤相关的下丘脑神经变性的治疗潜力提供新的见解。