Heritable Neurodegenerative and Autoimmune Disorders

遗传性神经退行性疾病和自身免疫性疾病

• 批准号: 7968539
• 负责人: ANIL B MUKHERJEE
• 金额: $ 109.56万
• 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/7968539
• 关键词: Acetylcysteine; Amino Acids; Anesthesia procedures; Anti-Inflammatory Agents; Apoptosis; Ascaridil; Asthma; Astrocytes; Autoimmune Diseases; Binding Sites; Birth; Bradycardia; Brain; Cell Line; Cells; Ceramidase; Ceramides; Ceroid; Cessation of life; Characteristics; Chemicals; Child; Childhood; Clara cell 10 kDa protein; Clinical; Clinical Trials; Collection; Complex; Cystagon; DNA; Disease; Disease Progression; Endoplasmic Reticulum; Enzymes; Equilibrium; Fibronectins; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genets; Goals; Henoch-Schoenlein Purpura; Heparin Binding; Hereditary Disease; Human; Immunoglobulin A; In Situ; Infantile neuronal ceroid lipofuscinosis; Inflammation; Inflammatory; Interleukin-6; Investigation; Kidney Diseases; Knock-out; Laboratories; Laboratory Research; Laboratory Study; Lead; Liquid substance; Lung; Lysophosphatidylcholines; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolism; Methods; Molecular; Molecular Chaperones; Mus; Mutation; Natural regeneration; Nerve Degeneration; Nervous System Heredodegenerative Disorders; Neuronal Ceroid-Lipofuscinosis; Neurons; Nuclear; Organ; Osteoblasts; Oxidative Stress; Pancreas; Pathogenesis; Pathologic; Patients; Phagocytes; Pharmaceutical Preparations; Phenotype; Phospholipase A2; Phospholipases A; Phospholipids; Physiological; Production; Property; Prostaglandins; Proteins; Publications; Pulmonary Fibrosis; Rare Diseases; Recycling; Regulation; Reporting; Risk; Role; Signal Transduction; Simian virus 40; Sphingolipids; Spielmeyer-Vogt Disease; Staurosporine; Steroids; Synaptic Vesicles; Therapeutic; Time; Transcription Factor AP-2 Alpha; Transfection; Transgenic Organisms; Uteroglobin; Yin-Yang; abstracting; alpha helix; bench to bedside; cancer cell; caspase-9; cell motility; cyclooxygenase 2; developmental genetics; effective therapy; endoplasmic reticulum stress; human CASP4 protein; insight; knockout gene; lipocalin 1; natural hypothermia; neuroinflammation; neuron apoptosis; neuropathology; neurotransmission; novel; novel therapeutic intervention; palmitoyl-protein hydrolase; prevent; receptor; research study; response; therapeutic target; thioesterase PPT1 gene product; ward

The Section on Developmental Genetics conducts both laboratory and clinical investigations to understand the molecular mechanisms of genetic disorders of neurodegenerative, inflammatory and autoimmune diseases in order to develop novel and rational therapeutic approaches. Towards these goals, the laboratory research of this Section is focused on understanding the regulation and physiological functions of primarily two genes:(1) palmitoyl-protein thioesterase-1 (PPT1) and (2) uteroglobin (UG), also known as Clara cell 10 kDa protein (CC10). Mutations in the PPT1 gene lead to a lethal neurodegenerative storage disorder known as infantile neuronal ceroid lipofuscinosis (INCL). INCL belongs to a group of the most common (1 in 12,500 births) neurodegenerative storage disorders, cumulatively known as Batten disease. Mutations in 8 different genes are reported to cause various forms of Batten disease. There is no effective treatment for any of these diseases. Accordingly, our efforts are focused on understanding the molecular mechanisms of these diseases and to develop rational therapies. Laboratory investigations on INCL have led to a clinical trial, which is currently ongoing. Recently, using PPT1-knockout (PPT1-KO) mice that recapitulate virtually all clinical and pathologic features of INCL, we uncovered for the first time that PPT1-deficiency leads to endoplasmic reticulum (ER) and oxidative stresses leading to neuronal death. In addition we discovered that PPT1-deficiency disrupts synaptic vesicle recycling and causes a progressive decline in the synaptic vesicle (SV) pool, which leads to abnormal neurotransmission, characteristic of INCL. Further, actvation of astroglia leads to neuroinflammation, which contributes to the rapid progression of the disease. The results of our experiments not only provide insight into a complex mechanism of neurodegeneration in INCL but also identifies several potential therapeutic targets. Ongoing studies are attempting to develop novel therapeutic approaches for this disease. Publications: Levin, S.W., Baker, E., Gropman, A., Quezado, Z.M.N., Miao, N., Zhang, Z., Jollands, A., Di Capua, M. and Mukherjee, A.B. (2008) Patients with Infantile Neuronal Ceroid Lipofuscinosis are susceptible to developing Subdural Fluid Collections. Arch. Neurol (in press);Miao N, Levin SW, Baker EH, Caruso RC, Zhang Z, Gropman A, Koziol D, Wesley R, Mukherjee AB, Quezado ZM. (2009) Children with infantile neuronal ceroid lipofuscinosis have an increased risk of hypothermia and bradycardia during anesthesia. Anesth Analg. 109, 372-378.Kim, S.J., Zhang, Z., Lee, Y.C., Sarkar, C., Tsai, P.C., Dye, L. and Mukherjee, A.B. (2008) PPT1-deficiency impairs synaptic vesicle-recycling and regeneration contributing to INCL neuropathology. J. Clin. Invest. 118, 3075-3086.Saha, A., Kim, S.-J., Zhang, Z., Lee, Y.-C., Tsai, P.-C., Soung, J. and Mukherjee, A.B. (2008) Elevated expression of S100B and RAGE mediates neuroinflammation in INCL.FEBS Lett. 582, 3823-3831Chowdhury, B., Zhang, Z., and Mukherjee, A.B. (2008) Uteroglobin interacts with the heparin-binding site of fibronectin and prevents fibronectin-IgA complex formation found in IgA-nephropathy. FEBS Lett. 582, 611-615.Wei, H., Kim, S.J., Zhang, Z., Tsai, P.C., Choi, M.S., Wisniewski, K.E. and Mukherjee, A.B. (2008) ER- and oxidative-stresses are common mediators of cellular death in lysosomal storage disorders: Cytoprotective role of chemical chaperones. Hum. Mol. Genet. 17, 469-477.Zhang, Z., Lee, Y.C., Kim, S.J., Choi, M.S., Tsai, P.C., Saha, A., Wei, H, Xu, Y.J., Zhang, P., Heffer, A. and Mukherjee, A.B. (2007) Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration.Hum Mol Genet. 16, 837-847.Lee, Y.-C., Zhang, Z., Hitomi, E. and Mukherjee, A.B. (2006). Mice lacking uteroglobin are highly susceptible to developing pulmonary fibrosis. FEBS Lett. 580, 4515-4520, 2006. Kim SJ, Zhang Z, Hitomi E, Lee YC and Mukherjee A. B. Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL.Hum Mol Genet. 15, 1826-1834, 2006. Kim SJ, Zhang Z, Lee YC and Mukherjee AB.(2006) Palmitoyl-protein thioesterase-1deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. Hum Mol Genet. 15,1580-1586, 2006.Zhang Z, Kim SJ, Chowdhury B, Wang J, Lee YC, Tsai PC, Choi M. and Mukherjee AB.Interaction of uteroglobin with lipocalin-1 receptor suppresses cancer cell motility and invasion. Gene. 369, 66-71, 2006.Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Xu Y, Xiao YJ, Zhang P, Heffer A. and Mukherjee AB. (2006). Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Hum MolGenet. 15, 337-346, 2006.Eisenstein EM, Choi M (2006) Analysis of a uteroglobin gene polymorphism in childhood Henoch-Schonlein purpura. Pediatr Nephrol 21:782-4; Zhang, Z., Kim, S.-J., Lee, Y.-C., Ray, R., Wang, J.-Y., Chowdhury, B., Choi, M.S.,Tsai, P.-C. and Mukherjee, A.B. (2005) Interaction of Uteroglobin with Lipocalin-1 Receptor. Gene. 369:66-71, 2006.Mandal, A.K., Zhang, Z. and Mukherjee, A.B. Yin-yang: balancing act of prostaglandins with opposing functions to regulate inflammation. .J. Immunol, Cutting Edge. 75, 6271-6273, 2005.Choi, M. S., Anderson, M.A., Zhang, Z., Zimonjic, D.B., Popescu, N. and Mukherjee, A.B. Neutral ceramidase gene: Role in regulating ceramide-induced apoptosis. (2003) Gene315:113-122;Chandra, S., Davis, J.M., Drexler, S., Kowalewska, J., Koo, H. C., Chester, D., Pollack, S., Welch, R, Pilon, A. and Levine, C.R. (2003) Pediatr Res. (2003)54:509-515; Chowdhury B, Mantile-Selvaggi G, Miele L, Cordella-Miele E, Zhang Z, Mukherjee AB. Lys 43 and Asp 46 in alpha-helix 3 of uteroglobin are essential for its phospholipase A2 inhibitory activity. Biochem Biophys Res Commun. 2002, 295:877-83; Wang CY, Lei HJ, Huang CY, Zhang Z, Mukherjee AB, Yuan CJ. Induction of cyclooxygenase-2 by staurosporine through the activation of nuclear factor for IL-6 (NF-IL6) and activator protein 2 (AP2) in an osteoblast-like cell line. Biochem Pharmacol. 2002 Jul 15;64(2):177-84; Mandal AK, Zhang Z, Chou JY, Mukherjee AB. Pancreatic phospholipase A2 via its receptor regulates expression of key enzymes of phospholipid and sphingolipid metabolism. FASEB J. 2001 Aug;15(10):1834-6. No abstract available. Mandal AK, Zhang Z, Chou JY, Zimonjic D, Keck CL, Popescu N, Mukherjee AB. (2001) Molecular characterization of murine pancreatic phospholipase A(2). DNA Cell Biol.20(3):149-57; Zhang Z, Butler JD, Levin SW, Wisniewski KE, Brooks SS, Mukherjee AB. Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med. 2001 Apr;7(4):478-84. Momeda K, Zhang Z, Mukherjee AB, Dhanireddy R. A novel in situ method of SV40 transfection for the establishment of immortal pulmonary alveolartype II cell lines. Ann N Y Acad Sci. 2000;923:325-31. Chowdhury B, Mantile-Selvaggi G, Kundu GC, Miele L, Cordella-Miele E, Zhang Z, Mukherjee AB. Amino acid residues in alpha-helix-3 of human uteroglobin are critical for its phospholipase A2 inhibitory activity. Ann N Y Acad Sci. 2000;923:307-11. Review. No abstract available. Choi M, Zhang Z, Ten Kate LP, Collee JM, Gerritsen J, Mukherjee AB. Human uteroglobin gene polymorphisms and genetic susceptibility to asthma. Ann N Y Acad Sci. 2000;923:303-6. Zhang Z, Kundu GC, Zheng F, Yuan CJ, Lee E, Westphal H, Ward J, DeMayo F, Mukherjee AB. Insight into the physiological function(s) of uteroglobin by gene-knockout and antisense-transgenic approaches. Ann N Y Acad Sci. 2000;923:210-33;

发育遗传学部分同时进行实验室和临床研究，以了解神经退行性，炎症性和自身免疫性疾病的遗传疾病的分子机制，以开发新颖的治疗方法。为了这些目标，本节的实验室研究集中在理解两个基因的调节和生理功能上：（1）棕榈酰蛋白硫代硫代酯酶1（PPT1）和（2）子宫蛋白酶（UG），也称为Clara Cell 10 KDA蛋白（CC10）。 PPT1基因中的突变导致致命的神经退行性储存障碍，称为婴儿神经元蛋白脂肪促脂肪促脂肪促脂肪促脂蛋白（含）。包含属于最常见的一组（12,500个出生）神经退行性储存障碍，累积地称为巴顿疾病。据报道，8种不同基因的突变会引起各种形式的棕褐色疾病。这些疾病中没有有效的治疗方法。因此，我们的努力专注于理解这些疾病的分子机制并开发理性疗法。对含有的实验室调查导致了一项临床试验，该试验目前正在进行中。最近，使用PPT1-KNOCKOUT（PPT1-KO）小鼠概括了含有含的所有临床和病理特征，我们首次发现PPT1缺乏导致内质网（ER）和氧化应激导致神经元死亡。此外，我们发现PPT1缺乏症会破坏突触囊泡回收，并导致突触囊泡（SV）池的逐渐下降，这导致神经传递异常，含有含义的特征。此外，星形胶质细胞的作用会导致神经炎症，这有助于疾病的快速发展。我们的实验结果不仅可以深入了解含义中神经退行性的复杂机制，而且还鉴定了几种潜在的治疗靶标。正在进行的研究正在尝试开发这种疾病的新型治疗方法。出版物：S.W. Levin，E.Baker，E.，Gropman，A.，Quezado，Z.M.N.，Miao，N.，Zhang，Z.，Jollands，A. （2008）婴儿神经元蛋白脂肪促脂肪促脂肪促脂肪促肌动症患者易受到硬膜下液体的收集。拱。 Neurol（印刷中）； Miao N，Levin SW，Baker EH，Caruso RC，Zhang Z，Gropman A，Koziol D，Wesley R，Mukherjee AB，Mukherjee AB，Quezado ZM。 （2009年）婴儿神经蛋白脂肪促脂肪促脂肪促脂肪促脂肪促性的儿童在麻醉期间患有体温过低和心动过缓的风险增加。 Anesth肛门。 109，372-378.Kim，S.J.，Zhang，Z.，Lee，Y.C.，Sarkar，C.，Tsai，P.C.，Dye，L。和Mukherjee，A.B。 （2008）PPT1缺乏症会损害有助于神经病理学的突触囊泡回收和再生。 J. Clin。投资。 118，3075-3086.Saha，A.，Kim，S.-J.，Zhang，Z. （2008）S100B和RAGE的表达升高介导了含有inct。 582，3823-3831Chowdhury，B.，Zhang，Z。和Mukherjee，A.B。 （2008）子宫蛋白与纤连蛋白的肝素结合位点相互作用，并防止Iga-氯性病中发现的纤连蛋白-iga复合物的形成。 febs lett。 582，611-615.Wei，H.，Kim，S.J.，Zhang，Z.，Tsai，P.C.，Choi，M.S.，Wisniewski，K.E。和Mukherjee，A.B。 （2008）ER和氧化应力是溶酶体储存障碍中细胞死亡的常见介体：化学伴侣的细胞保护作用。哼。摩尔。基因。 17，469-477.Zhang，Z. （2007）CPLA2在缺乏PPT1的小鼠的大脑中生产溶血磷脂酰胆碱是吞噬细胞浸润的信号。 16，837-847.Lee，Y.-C.，Zhang，Z.，Hitomi，E。和Mukherjee，A.B。 （2006）。 缺乏子宫球蛋白的小鼠非常容易患肺纤维化。 febs lett。 580，4515-4520，2006。Kim SJ，Zhang Z，Hitomi E，Lee YC和Mukherjee A. B.内质网应激诱导的caspase-4激活介导了含有含有含量摩尔遗传的凋亡和神经变性。 15，1826-1834，2006。Kim SJ，Zhang Z，Lee YC和Mukherjee AB（2006）Palmityl-蛋白硫代西酯酶-1DCEDICATIONS导致Caspase-9的激活，并有助于含有快速的NeuroDegeneration。嗡嗡声摩尔基因。 15,1580-1586，2006年。基因。 369，66-71，2006.zhang Z，Lee YC，Kim SJ，Choi MS，Tsai PC，Xu Y，​​Xiao YJ，Zhang P，Heffer A.和Mukherjee AB。 （2006）。棕榈酰蛋白硫代酶-1缺乏症介导了含有含的蛋白质反应和神经元凋亡的激活。嗡嗡声molgenet。 15，337-346，2006.Eisenstein EM，Choi M（2006）儿童henoch-Schonlein purpura中子宫球蛋白基因多态性的分析。小儿肾上腺素21：782-4;张，Z.和Mukherjee，A.B。 （2005）子宫球蛋白与脂肪蛋白-1受体的相互作用。基因。 369：66-71，2006。阴阳：平衡前列腺素的行为与相反的功能以调节炎症。 .J。免疫，尖端。 75，6271-6273，2005.Choi，M.S.，Anderson，M.A.，Zhang，Z.中性神经酰胺酶基因：调节神经酰胺诱导的细胞凋亡的作用。 （2003）Gene315：113-122; Chandra，S.，Davis，J.M.，Drexler，S.，Kowalewska，J.，Koo，H.C.，Chester，Chester，D.，Pollack，S.，Welch，R，Pilon，R，Pilon，A。和Levine，A。 （2003）54：509-515; Chowdhury B，Mantile-Selvaggi G，Miele L，Cordella-Miele E，Zhang Z，Mukherjee AB。子宫球蛋白的α-螺旋3中的LYS 43和ASP 46对于其磷脂酶A2抑制活性至关重要。 Biochem Biophys Res Commun。 2002，295：877-83; Wang Cy，Lei HJ，Huang CY，Zhang Z，Mukherjee AB，Yuan CJ。通过核因子在成骨细胞样细胞系中通过核因子的激活（NF-IL6）和激活蛋白2（AP2）通过核因子的激活来诱导环氧合酶-2。 Biochem Pharmacol。 2002年7月15日； 64（2）：177-84； Mandal AK，Zhang Z，Chou JY，Mukherjee AB。胰腺磷脂酶A2通过其受体调节磷脂和鞘脂代谢的关键酶的表达。 Faseb J. 2001年8月； 15（10）：1834-6。没有抽象可用。 Mandal AK，Zhang Z，Chou JY，Zimonjic D，Keck CL，Popescu N，Mukherjee AB。 （2001）鼠胰腺磷脂酶A（2）的分子表征。 DNA细胞Biol.20（3）：149-57; Zhang Z，Butler JD，Levin SW，Wisniewski KE，Brooks SS，Mukherjee AB。药物的溶酶体ceroid消耗：对遗传性神经退行性疾病的治疗意义。 Nat Med。 2001年4月； 7（4）：478-84。 Momeda K，Zhang Z，Mukherjee AB，DhaniriddyR。用于建立不朽肺肺单元II细胞系的SV40转染的小说。 Ann n y Acad Sci。 2000; 923：325-31。 Chowdhury B，Mantile-Selvaggi G，Kundu GC，Miele L，Cordella-Miele E，Zhang Z，Mukherjee AB。人子宫球蛋白的α-螺旋3中的氨基酸残基对于其磷脂酶A2抑制活性至关重要。 Ann n y Acad Sci。 2000; 923：307-11。审查。没有抽象可用。 Choi M，Zhang Z，Ten Kate LP，Collee JM，Gerritsen J，Mukherjee AB。人子宫球蛋白基因多态性和对哮喘的遗传敏感性。 Ann n y Acad Sci。 2000; 923：303-6。 Zhang Z，Kundu GC，Zheng F，Yuan CJ，Lee E，Westphal H，Ward J，Demayo F，Mukherjee AB。通过基因敲除和反义转基因方法来洞悉子宫球蛋白的生理功能。 Ann n y Acad Sci。 2000; 923：210-33;