Neuroendocrine Regulation of Metabolism and Neurocognition

代谢和神经认知的神经内分泌调节

• 批准号: 8553979
• 负责人: Joan C. Han
• 金额: $ 40.28万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553979
• 关键词: 11p13; Adult; Age; Agonist; Alstrom syndrome; Amputation; Animal Model; Animals; Autistic Disorder; BDNF gene; Bardet-Biedl Syndrome; Behavior; Behavioral; Blood Circulation; Body Weight; Body mass index; Brain-Derived Neurotrophic Factor; Cerebrum; Child; Chromosomes; Cilia; Cognitive; Collaborations; Correlation Studies; Defect; Desire for food; Detection; Development; Developmental Disabilities; Diagnosis; Disease; Etiology; Failure; Functional disorder; Gene Deletion; General Population; Genes; Genotype; Goals; Growth; Hereditary Disease; High Prevalence; Homeostasis; Human; Hyperphagia; Hypothalamic structure; Impaired cognition; Impairment; Infant; Joubert syndrome; Learning; Leptin; Leptin resistance; Medical center; Melanocortin 4 receptor mutation; Metabolism; Military Personnel; Morbid Obesity; Mus; Muscle hypotonia; Neonatal; Nervous system structure; Neuraxis; Neurocognition; Neurocognitive; Neurosecretory Systems; Nociception; Non obese; Nutritional; Obesity; Output; Pain; Pain Disorder; Pain Threshold; Parents; Pathway interactions; Patients; Perception; Peripheral; Phantom Limb Pain; Phenotype; Pilot Projects; Play; Prader-Willi Syndrome; Production; Questionnaires; Race; Regulation; Reporting; Research; Role; Satiation; Serum; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Stimulus; Sudden Death; Symptoms; Synaptic plasticity; Testing; WAGR Syndrome; WT1 gene; Weight Gain; autism spectrum disorder; brain tissue; cognitive function; cohort; energy balance; feeding; insight; leptin receptor; neurodevelopment; neuron development; obesity in children; response; response to injury; sex; trafficking

We have been conducting a comprehensive genotype-phenotype correlation study in patients with the WAGR (Wilms tumor, aniridia, genitourinary anomalies, mental retardation) syndrome, which is caused by heterozygous contiguous gene deletions of variable size in the chromosome 11p13 region. We had previously observed that haploinsufficiency for BDNF, the gene which encodes brain-derived neurotrophic factor, is associated with higher prevalence of childhood obesity and higher scores on a hyperphagia questionnaire (N Engl J Med 2008;359(9):918-27). BDNF is widely expressed throughout the nervous system and plays an important role in neuronal development and synaptic plasticity. In animal studies, BDNF appears to function downstream of the leptin signaling pathway to regulate appetite and energy balance. Our findings support the role of BDNF in human energy homeostasis. We have been conducting further studies to characterize the role of BDNF in neurocognitive function because Bdnf+/- mice are not only hyperphagic and obese, but also display learning deficits, behavioral abnormalities, and decreased thermal pain response. In a cohort of 31 patients with the WAGR syndrome, we observed that BDNF haploinsufficiency was associated with lower scores on a parent-completed questionnaire assessing behavior responses to injuries or illnesses considered painful to most people (p=0.03). These findings suggest that BDNF plays a role in human nociception. Studies are currently underway to examine detection and pain thresholds for hot and cold stimuli. Tests of cognitive and adaptive function, psychiatric symptoms, and autism spectrum diagnoses are also ongoing. A treatment study using a BDNF agonist in patients with BDNF haploinsufficiency is also under development. We have also been studying patients with Prader-Willi syndrome (PWS), which is caused by a lack of paternally expressed genes on chromosome 15q11-13. Patients with PWS typically present with hypotonia and poor feeding in the neonatal period followed by marked weight gain and severe hyperphagia between the ages of 1-5 years. PWS is also associated with cognitive impairment and behavioral abnormalities. We conducted a pilot study comparing 13 children with PWS versus 13 age/sex-matched lean controls and 13 age/sex/body mass index (BMI)-matched obese controls (J Clin Endocrinol Metab 2010;95(7):3532-6). We observed that patients with PWS had lower serum BDNF compared to the lean controls (p=0.03) as well as the obese controls (p=0.01). Lower serum BDNF suggests insufficient central nervous system production of BDNF because BDNF in peripheral circulation is believed to reflect cerebral output of BDNF. Decreased BDNF may be a potential cause for the disordered satiety and morbid obesity associated with PWS. BDNF insufficiency may also contribute to the neurocognitive abnormalities observed in PWS. We are currently conducting a study in a larger cohort of patients with PWS (25 infants, 25 non-obese children, and 25 obese children) and 75 BMI-matched controls to confirm these findings and to examine possible associations between cognitive function and serum BDNF concentrations. In collaboration with Dr. Biesecker's research group, we have been studying patients with Bardet-Biedl syndrome (BBS), a cilopathy associated with obesity. In animal models of cilia dysfunction, defects in leptin receptor trafficking and signaling have been reported. In our human studies (J Clin Endocrinol Metab 2011; 96(3):E528-35), we have observed that patients with BBS (n=50) have nearly two-fold higher serum leptin concentrations (p<0.001) compared with age/sex/race/BMI-matched control subjects (n=100). Hyperleptinemia out of proportion to degree of adiposity suggests that leptin resistance may be the causative etiology of obesity in BBS. We are currently seeking to replicate this observation in patients with Alstrom and Joubert syndromes, disorders that are distinct from BBS but are also associated with cilia dysfunction. In addition, we are investigating the role of BDNF in other conditions associated with childhood obesity (e.g. melanocortin 4-receptor mutations) and/or neurocognitive impairment (e.g. autism spectrum disorders - in collaboration with Dr. Swedo's research group). We are also studying the role of single nucleotide polymorphisms of the BDNF gene locus in body weight regulation and cognitive function in healthy adults and children from the general population. In collaboration with Dr. Kleinman's research group, we are examining the associations of BDNF genotype with BMI and hypothalamic BDNF expression in cadaveric brain tissue from adults with sudden death. Because of BDNF's potential role in pain perception, we are also collaborating with resarchers at the Walter Reed National Military Medical Center to explore possible associations between BDNF and phantom limb pain in patients who have had amputations.

我们一直在进行WAGR（WILMS肿瘤，Aniridia，Genitiourinary Anamalies，心理障碍）综合征的患者中进行全面的基因型 - 表型相关研究，该研究是由杂合性连续性基因缺失引起的。 我们以前曾观察到，编码脑衍生的神经营养因子的基因BDNF的单倍症与女性肥胖症的较高患病率和较高的女性帕吉亚调查表（N Engl J Med 2008; 359; 359; 359（9）：918-27）有关。 BDNF在整个神经系统中广泛表达，并在神经元发育和突触可塑性中起重要作用。 在动物研究中，BDNF似乎在瘦素信号传导途径的下游起作用，以调节食欲和能量平衡。 我们的发现支持BDNF在人类能量稳态中的作用。 我们一直在进行进一步的研究来表征BDNF在神经认知功能中的作用，因为BDNF +/-小鼠不仅是倍感和肥胖，而且还表现出学习缺陷，行为异常和降低热疼痛反应。 在31例WAGR综合征患者的队列中，我们观察到BDNF单倍度不足与父母完整的问卷调查表中的分数较低有关，评估对大多数人的伤害或疾病的行为反应（P = 0.03）。 这些发现表明，BDNF在人伤害感受中起作用。 目前正在进行研究以检查对冷热刺激的检测和疼痛阈值。 认知和适应性功能，精神病症状和自闭症谱系诊断的测试也在进行中。 使用BDNF激动剂在BDNF单倍不足患者中使用BDNF激动剂的治疗研究也正在开发中。 我们还一直在研究prader-Willi综合征（PWS）的患者，该患者是由于缺乏在15q11-13染色体上缺乏父子表达的基因而引起的。 PWS患者通常出现在新生儿时期的低位症和喂养不良的患者，随后重量增长显着，年龄在1-5岁之间。 PWS还与认知障碍和行为异常有关。 我们进行了一项试点研究，比较了13名PWS与13岁儿童/性别匹配的精益控制和13岁的年龄/性别/体重指数（BMI）匹配的肥胖对照（J Clin Clin Endocrinol Metab 2010; 95（7）：3532-6 ）。 我们观察到，与瘦的对照组相比，PWS患者的血清BDNF较低（P = 0.03）以及肥胖对照（P = 0.01）。 血清较低的BDNF表明中枢神经系统的BDNF产生不足，因为据信BDNF被认为反映了BDNF的脑输出。 BDNF减少可能是与PW相关的饱腹感和病态肥胖症的潜在原因。 BDNF功能不全也可能导致PWS中观察到的神经认知异常。 我们目前正在对较大的PW患者（25名婴儿，25名非肥胖儿童和25名肥胖儿童）和75个BMI匹配的对照组进行研究，以确认这些发现并检查认知功能与血清BDNF之间的可能关联。浓度。 在与比塞克尔博士的研究小组合作的情况下，我们一直在研究Bardet-Biedl综合征（BBS）的患者，这是一种与肥胖相关的纤毛病。 在纤毛功能障碍的动物模型中，已经报道了瘦素受体运输和信号传导的缺陷。 在我们的人类研究（J Clin Clin Endocrinol Metab 2011; 96（3）：E528-35）中，我们观察到BBS患者（n = 50）的血清瘦素浓度（P <0.001）近两倍。 /性别/种族/BMI匹配对照对象（n = 100）。 与肥胖程度不成比例的高级血症表明，瘦素耐药性可能是BBS肥胖症的病因。 我们目前正在寻求在Alstrom和Joubert综合征患者中复制这种观察结果，这些疾病与BBS不同，但也与CILIA功能障碍有关。 此外，我们正在研究BDNF在与儿童肥胖有关的其他疾病中的作用（例如黑色素质蛋白4受体突变）和/或神经认知障碍（例如自闭症谱系障碍 - 与Swedo博士研究小组合作）。 我们还研究了BDNF基因基因座的单核苷酸多态性在健康成年人和一般人群的儿童体重调节和认知功能中的作用。 与克莱恩曼博士的研究小组合作，我们正在研究BDNF基因型与BMI和下丘脑BDNF表达的关联。由于BDNF在疼痛感知中的潜在作用，我们还与沃尔特·里德国家军事医疗中心的转化器合作，探索患有截肢患者的BDNF和幻影肢体疼痛之间的可能关联。