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Endocrine Regulation of Alcohol Intake

酒精摄入的内分泌调节

基本信息

批准号：
10289389
负责人：
Matthew Joseph Potthoff
金额：
$ 35.86万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10289389
关键词：
Alcohol consumption Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Animal Model Attenuated Brain Brain Diseases Cells Clinical Trials Cognitive Cognitive deficits Collaborations Data Defect Dementia Diabetes Mellitus Disease Progression Endocrine Energy Metabolism Exhibits FGFR1 gene Fatty acid glycerol esters Fibroblast Growth Factor Receptors Hippocampus (Brain)Homeostasis Hormones Human Hypothalamic structure Impaired cognition Impairment In Vitro Insulin Resistance Learning Link Liver Liver Circulation Mediating Memory Memory impairment Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Mitochondria Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Nutrient Obesity Oxidative Stress Pathologic Pathway interactions Patients Pharmacology Physiological Physiological Processes Play Process Production Regulation Research Research Personnel Resistance Rodent Role Signal Transduction Specificity Stress Thalamic structure Therapeutic Tissues Transgenic Mice United States Viral abeta accumulation base blood glucose regulation cholinergic neuron cognitive function drug candidate epidemiologic data excitatory neuron fibroblast growth factor 21 glucose metabolism glucose tolerance human old age (65+)improved in vivo insight insulin sensitivity insulin sensitizing drugs metabolic profile mimetics misfolded protein mitochondrial dysfunction mouse model nonhuman primate novel therapeutic intervention prevent receptor response restoration success tau Proteins

项目摘要

Project Summary / Abstract Alzheimer's disease is a progressive neurodegenerative brain disease characterized by impairment in cognitive function. Alzheimer's disease is the most common cause of dementia and an estimated 5.8 million people in the United States age 65 and older are living with Alzheimer's dementia in 2020 (alz.org). Accumulation of amyloid beta (Aβ), a misfolded protein, is a key pathological hallmark of Alzheimer's disease but drug candidates targeting Aβ pathways have yielded little success [1]. More recently, changes in metabolism, particularly glucose metabolism, have been identified as a common feature observed in Alzheimer's disease [2, 3]. Notably, approximately 80% of patients with Alzheimer's disease exhibit impairments in glucose tolerance [4]. These observations along with other epidemiological data have led to the postulation that Alzheimer's disease may, in part, be a metabolic disorder [3, 5]. Fibroblast growth factor 21 (FGF21) is an endocrine hormone that corrects metabolic dysfunction and reverses diabetes and obesity in animal models [6]. FGF21 is an important regulator of glucose homeostasis and is a potent insulin sensitizer. Clinical trials with FGF21 mimetics have also demonstrated the efficacy of targeting this pathway to improve metabolic profiles in humans [7]. Interestingly, recent data suggests that FGF21 administration may also prevent neurodegeneration [8-10] and pathological deficits in animal models of Alzheimer's disease [11-13]. While circulating FGF21 levels are derived primarily by the liver [14], our preliminary data reveals the unexpected discovery that FGF21 is also expressed in a very specific region of the central nervous system. Specifically, FGF21 is expressed in the retrosplenial cortex and can signal to the hippocampus and can regulate learning and memory. A previous study demonstrates that FGF21 is induced from neurons in response to mitochondrial stress [9], and we hypothesize that FGF21 induction in this region regulates metabolic processes to prevent neurodegeneration. Several lines of evidence suggest that during prolonged metabolic impairments, endogenous signaling of FGF21 may be impaired leading to a “FGF21 resistant state” [15]. Importantly, administration of pharmacological levels of FGF21 is sufficient to overcome this resistance and restore metabolic homeostasis [16]. In this proposal, we seek to explore whether endogenous FGF21 signaling is also impaired during Alzheimer's disease progression and whether restoration of central FGF21 signaling, via pharmacological administration of FGF21 or local induction of FGF21 via sustained adeno-associated viral delivery, is sufficient to attenuate the cognitive and pathological deficits in a mouse model of Alzheimer's disease. Together, these studies will provide a better understanding of this potential therapeutic approach to treat Alzheimer's Disease and its related dementias.

项目总结/摘要阿尔茨海默病是一种进行性神经退行性脑疾病，其特征在于认知功能障碍，功能阿尔茨海默病是痴呆症最常见的原因，据估计，美国65岁及以上的老年人在2020年患有阿尔茨海默氏痴呆症（alz.org）。淀粉样蛋白积聚 β（Aβ）是一种错误折叠的蛋白质，是阿尔茨海默病的关键病理标志，但候选药物针对Aβ通路的治疗取得了很少的成功[1]。最近，新陈代谢的变化，特别是葡萄糖代谢，已被确定为阿尔茨海默病中观察到的共同特征[2，3]。值得注意的是，大约80%的阿尔茨海默病患者表现出葡萄糖耐量受损[4]。这些沿着其他流行病学数据的观察已经导致了这样的假设，即阿尔茨海默病可能，部分，是一种代谢紊乱[3，5]。成纤维细胞生长因子21（FGF 21）是一种内分泌激素，代谢功能障碍和逆转糖尿病和肥胖的动物模型[6]。FGF 21是一种重要的调节因子是一种有效的胰岛素增敏剂。FGF 21模拟物的临床试验也证明了靶向该途径改善人体代谢谱的功效[7]。有趣的是，最近的数据表明，FGF 21给药还可以预防神经变性[8-10]和病理性神经变性[8-10]。阿尔茨海默病动物模型的缺陷[11-13]。虽然循环中的FGF 21水平主要来源于肝脏[14]，我们的初步数据揭示了一个意外的发现，即FGF 21也在一个非常重要的细胞中表达。中枢神经系统的特定区域。具体地，FGF 21在压后皮质中表达，可以向海马体发出信号，调节学习和记忆。先前的一项研究表明， FGF 21是响应线粒体应激而从神经元诱导的[9]，我们假设FGF 21诱导在这个区域调节代谢过程，以防止神经退化。一些证据表明在长期的代谢障碍期间，FGF 21的内源性信号传导可能受损，导致 “FGF 21抗性状态”[15]。重要的是，施用药理学水平的FGF 21足以克服这种阻力并恢复代谢稳态[16]。在本建议中，我们寻求探讨内源性FGF 21信号传导在阿尔茨海默病进展过程中也受损，通过药物给予FGF 21或通过局部诱导FGF 21，持续的腺相关病毒递送足以减轻患者的认知和病理缺陷，阿尔茨海默病的小鼠模型。总之，这些研究将使人们更好地了解这种潜力阿尔茨海默病及其相关痴呆症的治疗方法。