Heriditary Neurodegenerative Storage Disorders

遗传性神经退行性存储障碍

• 批准号: 8149254
• 负责人: ANIL B MUKHERJEE
• 金额: $ 138.18万
• 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/8149254
• 关键词: Acetylcysteine; Cessation of life; Disease; Heparin Binding; Nerve Degeneration; nerve stem cell

The Section on Developmental Genetics conducts both laboratory and clinical investigations to understand the molecular mechanisms of heritable neurodegenerative lysosomal storage disorders (LSDs) that primarily affect children. As a group, these disorders represent the most common (1 in 12,500 births) neurodegenerative LSDs and are called neuronal ceroid lipofuscinoses (NCLs), commonly 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. Currently, our investigations are focused on understanding the molecular mechanism(s) of infantile form of NCL or INCL, which is one of the most lethal and devastating disease. The children with INCL are normal at birth but by 11-18 months of age they develop psychomotor retardation and complete retinal blindness. By age four years these children manifest no brain activity. They remain in a vegetative state for another 6-8 yars before death. Our long-term goals are to utilize the knowledge gained from laboratory investigations to develop novel and effective therapeutic approaches to these diseases. Our laboratory investigations on INCL have led to a bench-to-bedside clinical trial, which is currently ongoing. Recently, using Ppt1-knockout (Ppt1-KO) mice that recapitulate virtually all clinical and pathological 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 regeneration causing a progressive decline in the synaptic vesicle (SV) pool, which leads to abnormal neurotransmission, characteristic of INCL. Further, we found that actvation of astroglia leads to neuroinflammation, which contributes to the rapid progression of the disease. Further, our recent studies have uncovered that autophagy is dysregulated in PPT1-deficient cells causing lysosomal storage. The results of our experiments not only provide insight into a complex mechanism(s) of neurodegeneration in INCL but also identifies several potential therapeutic targets. Publications: Saha A, Lee YC, Zhang Z, Chandra G, Su SB, Mukherjee AB. (2010) Lack of endogenous anti-inflammatory protein in mice enhances colonization of B16F10 melanoma cells in the lungs. J Biol Chem. 285,10822-10831; Kim SJ, Zhang Z, Saha A, Sarkar C, Zhao Z, Xu Y, Mukherjee AB. (2010) Omega-3 and omega-6 fatty acids suppress ER- and oxidative stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1. Neurosci Lett. 479, 292-296; Levin, S.W., Baker, E., Gropman, A., Quezado, Z.M.N., Miao, N., Zhang, Z., Jollands, A., Di Capua, M. and Mukherjee, A.B. (2009) Patients with Infantile Neuronal Ceroid Lipofuscinosis are susceptible to developing Subdural Fluid Collections. Arch. Neurol 66(12):1567-71; 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; 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, 337-346Wei, 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.-CC., 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.

发育遗传学部分进行实验室和临床研究，以了解主要影响儿童的可遗传神经退行性溶酶体储存障碍（LSD）的分子机制。作为一个组，这些疾病代表了最常见的（12,500个出生）的神经退行性LSD，称为神经元蛋白脂肪糖蛋白酶（NCLS），通常称为巴顿疾病。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。目前，我们的研究集中在理解NCL或含有婴儿形式的分子机制上，这是最致命和毁灭性疾病之一。患有包含的儿童出生时正常，但是到11-18个月大时，他们会发展出精神病性迟缓和完全视网膜失明。到四岁时，这些孩子没有大脑活动。他们在死亡前仍处于营养状态，再进行6-8码。我们的长期目标是利用实验室调查中获得的知识来开发新颖有效的治疗方法对这些疾病。我们对含含的实验室调查导致了一项底层临床试验，该试验目前正在进行中。最近，使用PPT1敲除（PPT1-KO）小鼠概括了含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）和导致神经元死亡的氧化应激。此外，我们发现PPT1缺陷会破坏突触囊泡的回收和再生，导致突触囊泡（SV）池的逐渐下降，这导致神经传递异常，是含有含的特征。此外，我们发现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。此外，我们最近的研究发现，自噬在PPT1缺陷细胞中引起溶酶体储存的失调。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。出版物：Saha A，Lee YC，Zhang Z，Chandra G，Su SB，Mukherjee AB。 （2010）小鼠中缺乏内源性抗炎蛋白会增强肺中B16F10黑色素瘤细胞的定殖。 J Biol Chem。 285,10822-10831; Kim SJ，Zhang Z，Saha A，Sarkar C，Zhao Z，Xu Y，​​Mukherjee AB。 （2010年）Omega-3和Omega-6脂肪酸抑制缺乏PPT1小鼠的培养神经元和神经元祖细胞中的ER和氧化应激。 Neurosci Lett。 479，292-296; Levin，S.W.，E.Baker，E.，Gropman，A. （2009）婴儿神经元蛋白脂肪促脂肪促脂肪促脂肪促脂肪促肌张力的患者易受到硬膜下液的收集。拱。 Neurol 66（12）：1567-71; Miao N，Levin SW，Baker EH，Caruso RC，Zhang Z，Gropman A，Koziol D，Wesley R，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; 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。 15，337-346Wei，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.-CC.，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。