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.

人脑发育和衰老过程中花生四烯酸和二十二碳六烯酸级联酶基因表达的协调。多不饱和花生四烯酸和二十二碳六烯酸（AA 和 DHA）参与整个生命过程中的神经可塑性和神经传递。每一种都通过独立但相互作用的代谢级联中的酶促反应进行代谢。我们发现 AA 和 DHA 通路基因协调表达，是人类大脑发育和衰老过程中级联相互作用的基础。我们使用公开的 BrainCloud 人类非病理性前额皮质基因表达数据库来量化与 AA 和 DHA 代谢相关的 34 个基因的 mRNA 表达的出生后年龄变化。表达模式分为发育（0 至 20 岁）和衰老（21 至 78 岁）区间。细胞质磷脂酶 A2 (cPLA2)、环氧合酶 (COX)-1 和 -2 以及其他 AA 级联酶的基因表达在发育过程中与年龄密切相关，但在衰老过程中与年龄相关性较小。 DHA 级联酶的表达相互关联性较小，但经常以与 AA 级联基因表达相反的方向变化。因此，大脑发育和衰老期间与年龄相关的基因协调表达可能是 AA 和 DHA 级联酶耦合变化的基础，并且很大程度上是通过远程转录调节发生的。健康的大脑老化不会表现出在阿尔茨海默病中发现的 PLA2G4 或 PTGS2 表达上调。 (1) 人脑发育和衰老过程中参与磷脂酰肌醇信号通路的基因的相关表达变化。磷酸肌醇是参与多种细胞过程的重要信号分子，包括神经传递、自噬、细胞凋亡、细胞生长和膜运输。与之前的报告一样，我们正在使用人类前额皮质的 BrainCloud 数据库研究参与磷酸肌醇信号传导的 49 个基因。显示每对基因之间相关性的热图显示了一组高度相互关联的基因，这些基因在发育和衰老期间也以不同的方式在功能上相关。这项工作正在进行中。 人脑发育和衰老过程中背外侧前额叶皮层神经炎症和细胞信号标记的协调基因表达。我们使用来自人类前额皮质的大规模微阵列数据集BrainCloud，将人脑中炎症、突触和神经营养基因的表达水平在整个生命周期中协调起来，并成为表型网络或级联变化的基础，该数据集分为发育期（0至21岁，87个大脑）和衰老期（22至78岁，144个大脑）。 39 个基因的表达水平在整个生命周期中遵循不同的轨迹，并且在两个区间内的相关性不同。尽管基因产物在两个时间段中的作用不同，但在发育和衰老过程中，三个相似的基因组或基因簇内的许多变化是相互关联的。在发育过程中，变化与报告的神经元丢失、树突生长和修剪以及小胶质细胞事件有关； TLR4、IL1R1、NFKB1、MOBP、PLA2G4A 和 PTGS2 的表达在生命的最初几年增加，而突触基因 GAP43 和 DBN1 的表达在达到平台之前下降。在衰老过程中，NFkB1、TRAF6、TLR4、IL1R1、TSPO 和 GFAP 等潜在促炎基因的表达上调，但 BDNF、NGF、PDGFA、SYN 和 DBN1 等神经营养和突触完整性基因的表达下调。该作品正在提交出版。 精神分裂症患者灰白质中脑源性神经营养因子的老化趋势。我们假设 BDNF 在精神分裂症中报告的异常大脑老化中发挥作用。我们通过测量 20 名精神分裂症患者和 20 名匹配对照成人寿命（从 20 岁到 80 岁）死后前额皮质 (PFC) 灰质和胼胝体膝部白质中的 BDNF 蛋白水平来检验这一假设。在对照组和患者中，PFC 灰质 BDNF 蛋白水平随着年龄的增长而显着下降，而白质中的 BDNF 蛋白水平在两组中均没有随着年龄的增长而显着下降。对照组的 PFC BDNF 从 20 岁到 80 岁呈线性下降。在精神分裂症中，年轻患者的下降率类似呈线性，但老年患者并未出现下降。因此，随着年龄的增长，PFC BDNF 并没有遵循精神分裂症患者的正常线性下降，这可能代表由于早期下降而产生的底线效应，或者是老年患者捐赠者的幸存者群体，他们不太容易受到精神分裂症相关的病理性衰老过程的影响。已提交出版。 亨廷顿病中的脑脊液肌醇。亨廷顿舞蹈症 (HD) 是一种破坏性的遗传性大脑疾病。脑脊液 (CSF) 中与 HD 相关的生物标志物的识别将在了解 HD 的自然史、进行临床药物试验以及识别大脑和外周的致病过程方面具有多种应用。我们已经发表了一种测量脑脊液多元醇的分析方法，并用它来显示唐氏综合症患者脑脊液中的肌醇升高，但阿尔茨海默病患者的脑脊液中肌醇没有升高（Shetty 等人，J Clin Invest, 99, 542, 1995）。在这项与大学 Blair Levitt 博士的合作研究中。不列颠哥伦比亚省，我们正在测试这样的假设：与对照组相比，HD 患者的脑脊液肌醇水平会增加。 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。虽然抗逆转录病毒疗法的出现降低了最严重的 HIV 相关认知功能障碍 (HAND) 的发病率，但在针对病毒控制患者的不同人群研究中，HAND 患病率估计为 20%-69%。有证据表明，大脑的 HIV-1 感染会刺激先天性和适应性免疫系统，并引起神经炎症，涉及细胞因子的过量分泌，包括激活的小胶质细胞白细胞介素 1β (IL-1β)，从而刺激反应性星形胶质细胞上的 IL-1 受体，并启动可能导致 HAND 并涉及花生四烯酸的神经病理级联反应。 IL-1 受体细胞因子 IL-1 家族的刺激会诱导包括 IL-6 在内的 IL-1 靶基因的表达，从而引发神经炎症级联反应。在 NINDS 和 NIAID 的合作中，与 Drs. Avindra Nath 和 Chuen-Yen Lau，我们正在准备一项临床方案，以测试给予 Anakinra（一种重组非糖基化人白细胞介素 1 受体拮抗剂）是否会中断接受 ART 的 HIV-1 受试者的神经炎症级联反应并减轻 HAND。