Lipids in Human Brain Disease

人脑疾病中的脂质

• 批准号: 8931543
• 负责人: Stanley I. Rapoport
• 金额: $ 54.67万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 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/8931543
• 关键词: 20 year old; 21 year old; Adult; Age; Age Reporting; Age-Years; Aging; Aging-Related Process; Alzheimer' s Disease; Animal Model; Apoptosis; Arachidonic Acids; Astrocytes; Autophagocytosis; Autopsy; Biochemical Reaction; Biological Markers; Bipolar Disorder; Brain; Brain Diseases; Brain-Derived Neurotrophic Factor; British Columbia; Cell physiology; Cerebrospinal Fluid; Clinical; Clinical Protocols; Collaborations; Coupled; Cytosolic Phospholipase A2; Data Set; Databases; Development; Disease; Distant; Docosahexaenoic Acids; Down Syndrome; Enzymes; Event; Family; Floor; Functional disorder; Gene Cluster; Gene Expression; Gene Targeting; Genes; Glial Fibrillary Acidic Protein; Goals; Growth; HIV; HIV-1; Heating; Hereditary Disease; Human; Huntington Disease; IL1R1 gene; Immune system; Impaired cognition; Incidence; Infection; Inflammatory; Inositol; Interleukin-1; Interleukin-6; Life; Lipids; Longevity; Maps; Measures; Membrane Protein Traffic; Metabolic; Metabolism; Microglia; National Institute of Allergy and Infectious Disease; National Institute of Neurological Disorders and Stroke; Natural History; Neuronal Plasticity; PDGFA gene; PLA2G4A gene; PTGS2 gene; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phosphatidylinositols; Play; Population Study; Prefrontal Cortex; Prevalence; Process; Proteins; Publications; Publishing; Recombinants; Reporting; Risk Factors; Role; Schizophrenia; Signal Pathway; Signal Transduction; Signaling Molecule; Structure of genu of corpus callosum; Survivors; Symptoms; Synapses; TLR4 gene; TRAF6 gene; Testing; Transcriptional Regulation; Up-Regulation; Work; age related; aging brain; anakinra; analytical method; antiretroviral therapy; brain tissue; cell growth; cohort; cyclooxygenase 1; cytokine; design; excitotoxicity; gray matter; lipid metabolism; mRNA Expression; myoinositol; neuroinflammation; neuron loss; neurotransmission; older patient; pathological aging; polyol; postnatal; receptor; trend; white matter

COORDINATION OF GENE EXPRESSION OF ARACHIDONIC AND DOCOSAHEXAENOIC ACID CASCADE ENZYMES DURING HUMAN BRAIN DEVELOPMENT AND AGING. The polyunsaturated arachidonic and docosahexaenoic acids (AA and DHA) participate in neuroplasticity and neurotransmission throughout life. Each is metabolized via enzymatic reactions within separate but interacting metabolic cascades. We showed that AA and DHA pathway genes are coordinately expressed and underlie cascade interactions during human brain development and aging. We used the publically available BrainCloud database for human non-pathological prefrontal cortex gene expression to quantify postnatal age changes in mRNA expression of 34 genes involved in AA and DHA metabolism. Expression patterns were split into Development (0 to 20 years) and Aging (21 to 78 years) intervals. Expression of genes for cytosolic phospholipases A2 (cPLA2), cyclooxygenases (COX)-1 and -2, and other AA cascade enzymes, correlated closely with age during Development, less so during Aging. Expression of DHA cascade enzymes was less inter-correlated, but often changed in the opposite direction to expression of AA cascade genes. Thus, coordinated age-related gene expression during the brain Development and Aging intervals likely underlies coupled changes in enzymes of the AA and DHA cascades and largely occur through distant transcriptional regulation. Healthy brain aging does not show upregulation of PLA2G4 or PTGS2 expression, which was found in Alzheimer's disease. (1) CORRELATED EXPRESSION CHANGES IN GENES INVOLVED IN PHOSPHOINOSITIDE SIGNALING PATHWAYS DURING HUMAN BRAIN DEVELOPMENT AND AGING. Phosphoinositides are important signaling molecules that participate in diverse cellular processes, including neurotransmission, autophagy, apoptosis, cell growth, and membrane trafficking. As in the prior report, we are studying 49 genes involved in phosphoinositide signaling using the BrainCloud database for the human prefrontal cortex. Heat maps showing correlations between each pair of genes showed groups of highly intercorrelated genes that were also functionally related in different ways during the Development and Aging periods. This work is in progress. COORDINATED GENE EXPRESSION OF NEUROINFLAMMATORY AND CELL SIGNALING MARKERS IN DORSOLATERAL PREFRONTAL CORTEX DURING HUMAN BRAIN DEVELOPMENT AND AGING. We showed that expression levels of inflammatory, synaptic, and neurotrophic genes in the human brain are coordinated over the lifespan and underlie changes in phenotypic networks or cascades, using a large-scale microarray dataset from human prefrontal cortex, BrainCloud, divided into Development (0 to 21 years, 87 brains) and Aging (22 to 78 years, 144 brains) intervals. Expression levels for 39 genes followed different trajectories over the lifespan, and were correlated differently in the two intervals. Many changes were intercorrelated within three similar groups or clusters of genes during both Development and Aging, despite different roles of the gene products in the two intervals. During Development, changes were related to reported neuronal loss, dendritic growth and pruning, and microglial events; TLR4, IL1R1, NFKB1, MOBP, PLA2G4A, and PTGS2 expression increased in the first years of life, while expression of synaptic genes GAP43 and DBN1 decreased, before reaching plateaus. During Aging, expression was upregulated for potentially pro-inflammatory genes such as NFkB1, TRAF6, TLR4, IL1R1, TSPO, and GFAP, but downregulated for neurotrophic and synaptic integrity genes such as BDNF, NGF, PDGFA, SYN, and DBN1. This work is being submitted for publication. AGING TRENDS OF BRAIN-DERIVED NEUROTROPHIC FACTOR IN THE GRAY AND WHITE MATTER OF SCHIZOPHRENIA PATIENTS. We hypothesized that BDNF plays a role in the abnormal brain aging reported in schizophrenia. We tested this hypothesis by measuring BDNF protein levels in postmortem gray matter of prefrontal cortex (PFC) and white matter of the genu of the corpus callosum from 20 schizophrenia patients and 20 matched controls across the adult lifespan, from 20-80 years. PFC gray matter BDNF protein levels declined significantly with age in both controls and patients, while BDNF in white matter did not decrease significantly with age in either group. PFC BDNF decreased linearly from 20 to 80 years of age in controls. In schizophrenia, the rate of decline was similarly linear in younger patients but a decline did not occur in older patients. Thus, PFC BDNF did not follow a normative linear decline in schizophrenia patients as they grow older, which may represent a floor effect due to earlier decline, or a survivor cohort of older patient donors who are less susceptible to a schizophrenia-related pathological aging process. Submitted for publication. CEREBROSPINAL FLUID MYOINOSITOL IN HUNTINGTON DISEASE. Huntington disease (HD) is a devastating hereditary disorder of the brain. Identification of HD-associated biomarkers in cerebrospinal fluid (CSF) would have multiple applications in understanding the natural history of HD, in performing clinical drug trials and in identifying pathogenic processes in the brain and the periphery. We have published an analytical method to measure CSF polyols, and used it to show elevated myoinositol in CSF from Down syndrome but not Alzheimer disease patients (Shetty et al. J Clin Invest, 99, 542, 1995). In this collaborative study with Dr. Blair Levitt at Univ. British Columbia, we are testing the hypothesis that increased levels of CSF myo-inositol will be found in HD patients compared with controls. ANAKINRA, A RECOMBINANT HUMAN IL-1 RECEPTOR ANTAGONIST, FOR TREATING NEUROINFLAMMATION IN HIV-1 INFECTION. While the advent of antiretroviral therapy has led to a decreased incidence of the most severe form of HIV associated cognitive dysfunction (HAND), HAND prevalence is estimated at 20%-69% in different population studies of virally-controlled patients. There is evidence that HIV-1 infection of the brain stimulates the innate and adaptive immune systems, and causes neuroinflammation involving excess secretion of cytokines including interleukin-1β (IL-1β) by activated resident microglia, thereby stimulating IL-1 receptors on reactive astrocytes, and initiating a neuropathological cascade that may contribute to HAND and involve arachidonic acid. Stimulation by the IL-1 family of cytokines of the IL-1 receptor induces expression of IL-1 target genes including IL-6, initiating a neuroinflammatory cascade. In a collaboration involving NINDS and NIAID, with Drs. Avindra Nath and Chuen-Yen Lau, we are preparing a clinical protocol to test if administering Anakinra, a recombinant non-glycosylated human interleukin-1 receptor antagonist, will interrupt the neuroinflammatory cascade in HIV-1 subjects on ART and mitigate HAND.

在人脑发育和衰老过程中，基因表达的基因表达和二十六烯酸甲酸级联酶的酶。多不饱和的蛛网膜化和二十二碳六烯酸（AA和DHA）一生都参与神经塑性和神经传递。每种都在单独但相互作用的代谢级联反应中通过酶促反应代谢。我们表明，在人脑发育和衰老期间，AA和DHA途径基因在人脑发育和衰老过程中的级联相互作用是协调的。我们使用公开可用的BrainCloud数据库用于人类非病理前额叶皮层基因表达，以量化AA和DHA代谢参与34个基因的mRNA表达的产后年龄变化。表达模式分为发育（0至20年）和衰老（21至78年）。胞质磷脂酶A2（CPLA2），环氧酶（COX）-1和-2的基因表达，以及其他AA级联酶，与发育过程中的年龄紧密相关，在衰老过程中较少。 DHA级联酶的表达较不相关，但通常朝着AA级联基因的表达相反。因此，与年龄相关的基因表达在大脑发育和衰老间隔内可能是AA和DHA级联酶的酶变化的基础，并且在很大程度上通过远处的转录调节发生。健康的大脑衰老不会显示出在阿尔茨海默氏病中发现的PLA2G4或PTGS2表达的上调。 （1） 在人脑发育和衰老过程中，与磷酸肌醇信号通路有关的基因的表达变化相关。磷酸肌醇是参与各种细胞过程的重要信号分子，包括神经传递，自噬，凋亡，细胞生长和膜运输。与先前的报告一样，我们使用人类前额叶皮层的Braincloud数据库研究了49个参与磷酸肌醇信号的基因。显示每对基因之间相关性的热图显示，在发育和衰老期间，它们在功能上也以不同的方式相关。这项工作正在进行中。 在人脑发育和衰老期间，背外侧前额叶皮层中神经炎症和细胞信号标志物的协调基因表达。我们表明，人脑中炎症，突触和神经营养基因的表达水平在整个生命周期内得到了协调，并且使用了大型的微阵列数据集在人类前额叶皮层（87年）和22年（22年）间隔（22至78年）中，使用了人类前额叶皮层，分为BrainCloud（braincloud）的大型微阵列数据集，并在表型网络或级联反应的基础上进行协调。 39个基因的表达水平在整个寿命中遵循不同的轨迹，并且在两个间隔中以不同的方式相关。尽管基因产物在两个间隔中的作用不同，但在发育和衰老过程中，在三个相似的基因或基因簇中相关的许多变化是相互关联的。在开发过程中，变化与报道的神经元丧失，树突状的生长和修剪以及小胶质事件有关。 TLR4，IL1R1，NFKB1，MOBP，PLA2G4A和PTGS2表达在生命的头几年中增加，而突触基因的表达GAP43和DBN1的表达却降低，然后降低，然后到达高原。在衰老过程中，对于潜在的促炎基因，例如NFKB1，TRAF6，TLR4，IL1R1，TSPO和GFAP，表达上调，但对于神经营养和突触完整性基因，例如BDNF，NGF，PDGFA，PDGFA，SYN和DBN1，但对于神经营养和突触完整性基因而下调。这项工作正在提交出版。 精神分裂症患者的灰色和白质脑衍生的神经营养因子的衰老趋势。我们假设BDNF在精神分裂症报道的异常脑衰老中起作用。我们通过测量前额叶皮层（PFC）（PFC）的BDNF蛋白水平和来自20-80岁的成人寿命的20种匹配对照组的BDNF蛋白水平和call体的白色质量。 PFC灰质BDNF蛋白水平随着对照和患者的年龄而显着下降，而白质的BDNF均未随着这两组年龄的年龄而显着降低。 PFC BDNF在对照中从20岁到80岁线性降低。在精神分裂症中，年轻患者的下降速度类似，但老年患者没有下降。因此，PFC BDNF随着年龄的增长而没有遵循精神分裂症患者的规范性线性下降，这可能代表了由于早期下降而导致的地板效应，或者是幸存者队列的老年患者捐助者，这些捐助者对与精神分裂症相关的病理衰老过程不太容易受到影响。提交出版。 亨廷顿疾病中的脑脊液肌醇。亨廷顿病（HD）是大脑毁灭性的遗传疾病。在脑脊液（CSF）中鉴定与HD相关的生物标志物在理解HD的自然病史，进行临床药物试验以及识别大脑和周围的致病过程方面具有多种应用。我们已经发表了一种分析方法来测量CSF多元醇，并将其显示出唐氏综合症的CSF中肌醇的升高，但不是阿尔茨海默氏病患者（Shetty等人J Clin Invest，99，542，1995）。在与Univ的Blair Levitt博士的合作研究中。不列颠哥伦比亚省，我们正在测试以下假设：与对照组相比，在HD患者中发现CSF肌醇水平升高。 Anakinra是一种重组人IL-1受体拮抗剂，用于治疗HIV-1感染中的神经炎症。尽管抗逆转录病毒疗法的出现导致最严重的HIV相关认知功能障碍（HARD）的发生率降低，但在病毒控制的患者的不同人群研究中，手患病率估计为20％-69％。 There is evidence that HIV-1 infection of the brain stimulates the innate and adaptive immune systems, and causes neuroinflammation involving excess secretion of cytokines including interleukin-1β (IL-1β) by activated resident microglia, thereby stimulating IL-1 receptors on reactive astrocytes, and initiating a neuropathological cascade that may contribute to HAND and involve arachidonic acid. IL-1受体的IL-1家族刺激IL-1家族诱导包括IL-6在内的IL-1靶基因的表达，启动神经炎症级联反应。在涉及Ninds和Niaid的合作中，与Drs。 Avindra Nath和Chuen-Yen Lau，我们正在准备一种临床方案，以测试Anakinra，如果施用Anakinra，是一种重组非糖基化的人介毒素1受体拮抗剂，将中断ART和Mitigation Hand和Mitigation Hand的HIV-1受试者中的神经毒素性级联反应。