Neuroendocrine Regulation of Metabolism and Neurocognition

代谢和神经认知的神经内分泌调节

• 批准号: 8941541
• 负责人: Joan C. Han
• 金额: $ 21.18万
• 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/8941541
• 关键词: 11p13; Adaptive Behaviors; 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; Collaborations; Correlation Studies; Defect; Desire for food; Development; Developmental Disabilities; Diagnostic; 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; Intelligence quotient; Interview; 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; 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; Smith Magenis syndrome; Sudden Death; Synaptic plasticity; WAGR Syndrome; WT1 gene; Weight Gain; autism spectrum disorder; brain tissue; cognitive function; cohort; energy balance; feeding; insight; leptin receptor; meetings; neurodevelopment; neuron development; obesity in children; response; response to injury; sex; social; 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. We have observed that among subjects with WAGR syndrome, BDNF haploinsufficiency is associated with 14-point lower Vineland Adaptive Behaviour Compose score and 20-point lower intelligence quotient, as well as greater social impairment and higher percentage meeting cut-off score for autism on Autism Diagnostic Interview-Revised. BDNF haploinsufficiency is also associated with lower scores on a parent-completed questionnaire assessing behavior responses to injuries or illnesses considered painful to most people. These findings suggest that BDNF plays a role in human cognitive functioning and nociception. 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 Smith-Magenis syndrome) 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.

我们一直在对 WAGR（肾母细胞瘤、无虹膜、泌尿生殖异常、智力迟钝）综合征患者进行全面的基因型-表型相关性研究，该综合征是由染色体 11p13 区域中不同大小的杂合连续基因缺失引起的。 我们之前观察到，BDNF（编码脑源性神经营养因子的基因）的单倍体不足与儿童肥胖症患病率较高和食欲亢进问卷得分较高有关（N Engl J Med 2008;359(9):918-27） 。 BDNF 在整个神经系统中广泛表达，在神经元发育和突触可塑性中发挥重要作用。 在动物研究中，BDNF 似乎在瘦素信号通路下游发挥作用，调节食欲和能量平衡。 我们的研究结果支持 BDNF 在人体能量稳态中的作用。 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+/- 小鼠不仅食量过多和肥胖，而且还表现出学习缺陷、行为异常和热痛反应减弱。 我们观察到，在患有 WAGR 综合征的受试者中，BDNF 单倍体不足与 Vineland 适应性行为构成分数降低 14 分、智商降低 20 分、以及更大的社交障碍和更高的满足自闭症截止分数的百分比相关诊断访谈-修订版。 BDNF 单倍体不足还与家长填写的问卷中得分较低有关，该问卷评估了对大多数人认为痛苦的伤害或疾病的行为反应。 这些发现表明 BDNF 在人类认知功能和伤害感受中发挥作用。 一项使用 BDNF 激动剂治疗 BDNF 单倍体不足患者的治疗研究也在开发中。 我们还一直在研究普瑞德-威利综合征 (PWS) 患者，该综合征是由染色体 15q11-13 上缺乏父系表达基因引起的。 PWS 患者通常在新生儿期出现肌张力低下和喂养不良，随后在 1-5 岁期间出现体重明显增加和严重的食欲过盛。 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 儿童与 13 名年龄/性别匹配的瘦对照儿童和 13 名年龄/性别/体重指数 (BMI) 匹配的肥胖对照儿童 (J Clin Endocrinol Metab 2010;95(7):3532-6 ）。 我们观察到，与瘦对照者 (p=0.03) 和肥胖对照者 (p=0.01) 相比，PWS 患者的血清 BDNF 较低。 血清 BDNF 较低表明中枢神经系统产生的 BDNF 不足，因为外周循环中的 BDNF 被认为反映了大脑中 BDNF 的输出。 BDNF 减少可能是与 PWS 相关的饱腹感紊乱和病态肥胖的潜在原因。 BDNF 不足也可能导致 PWS 中观察到的神经认知异常。 我们目前正在对更大的 PWS 患者（25 名婴儿、25 名非肥胖儿童和 25 名肥胖儿童）和 75 名 BMI 匹配对照人群进行一项研究，以证实这些发现并检查认知功能与血清 BDNF 之间可能存在的关联浓度。 我们与 Biesecker 博士的研究小组合作，研究了 Bardet-Biedl 综合征 (BBS) 患者，这是一种与肥胖相关的纤毛病。 据报道，在纤毛功能障碍的动物模型中，瘦素受体运输和信号传导存在缺陷。 在我们的人体研究中 (J Clin Endocrinol Metab 2011; 96(3):E528-35)，我们观察到 BBS 患者 (n=50) 的血清瘦素浓度比年龄高出近两倍 (p<0.001) /性别/种族/BMI 匹配的对照受试者 (n=100)。 高瘦素血症与肥胖程度不成比例表明瘦素抵抗可能是 BBS 肥胖的病因。 我们目前正在寻求在阿尔斯特罗姆综合征和朱伯特综合征患者中复制这一观察结果，这些疾病与 BBS 不同，但也与纤毛功能障碍有关。 此外，我们正在研究 BDNF 在与儿童肥胖（例如黑皮质素 4 受体突变和 Smith-Magenis 综合征）和/或神经认知障碍（例如自闭症谱系障碍 - 与 Swedo 博士的研究小组合作）相关的其他疾病中的作用。 我们还在研究 BDNF 基因位点的单核苷酸多态性在健康成人和儿童的体重调节和认知功能中的作用。 我们与 Kleinman 博士的研究小组合作，研究 BDNF 基因型与 BMI 以及猝死成人尸体脑组织中下丘脑 BDNF 表达的关系。由于 BDNF 在疼痛感知中的潜在作用，我们还与沃尔特·里德国家军事医学中心的研究人员合作，探索 BDNF 与截肢患者幻肢痛之间可能存在的关联。

项目成果

Rapid and inexpensive screening of genomic copy number variations using a novel quantitative fluorescent PCR method.

• DOI: 10.1155/2013/704917
• 发表时间: 2013
• 期刊: Disease markers
• 作者: Stofanko M;Han JC;Elsea SH;Pena HB;Gonçalves-Dornelas H;Pena SD
• 通讯作者: Pena SD

Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) predicts height velocity in healthy children.

C 型钠尿肽 (NTproCNP) 的氨基末端前肽可预测健康儿童的身高速度。

• DOI: 10.1111/j.1365-2265.2012.04392.x
• 发表时间: 2012-09
• 期刊: Clinical endocrinology
• 影响因子: 3.2
• 作者: Olney RC;Permuy JW;Prickett TC;Han JC;Espiner EA
• 通讯作者: Espiner EA