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: 7333923
• 负责人: ANIL B MUKHERJEE
• 金额: --
• 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/7333923
• 关键词: Heritable; Neurodegenerative; Autoimmune; Disorders

The Section on Developmental Genetics conducts both laboratory and clinical investigations to understand the molecular mechanisms of complex 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) uteroglobin (UG), also known as Clara cell 10 kDa protein (CC10), and (2) palmitoyl-protein thioesterase-1 (PPT1). Inactivating mutations in the PPT1 gene is the genetic basis of infantile neuronal ceroid lipofuscinosis (INCL), also known as infantile Batten disease. INCL is a devastating neurodegenerative storage disease of childhood. for which there is no effective treatment. UG-knockout mice develop immunoglobulin A (IgA)-nephropathy, a primary renal glomerular disease that often lead to kidney failure. This disease also does not have an effective treatment. Laboratory investigations in INCL have led to a bench-to-bedside clinical trial, which is currently ongoing. Recently, using PPT1-knockout (PPT1-KO) mice, which recapitulates virtually all clinical and pathological features INCL, we uncovered, for the first time that tPPT1-deficiency leads to endoplasmic reticulum (ER) stress (ER stress), which activates the unfolded protein response mediating apoptotic death of neurons, a characteristic finding in INCL. The results of our experiments not onlt provide insight into a complex mechanism of neurodegeneration in INCL but also identifies several potential targets for the development of rational and novel therapeutic approaches for this uniformly fatal disease. **Publications: 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. Molecular characterization of murine pancreatic phospholipase A(2). DNA Cell Biol. 2001 Mar;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; Zhang Z, Mandal AK, Mital A, Popescu N, Zimonjic D, Moser A, Moser H, Mukherjee AB. Human acid ceramidase gene: novel mutations in Farber disease. Mol Genet Metab. 2000 Aug;70(4):301-9. Yuan CJ, Mandal AK, Zhang Z, Mukherjee AB. Transcriptional regulation of cyclooxygenase-2 gene expression: novel effects of nonsteroidal anti-inflammatory drugs. Cancer Res. 2000 Feb 15;60(4):1084-91. Zheng F, Kundu G, Zhang Z, Mukherjee AB, Ward J, DeMayo F. Identical glomerulopathy in two different mouse models of uteroglobin deficiency. Am J Kidney Dis. 2000 Feb;35(2):362-3. Mantile G, Fuchs C, Cordella-Miele E, Peri A, Mukherjee AB, Miele L Stable, long-term bacterial production of soluble, dimeric, disulfide-bonded protein pharmaceuticals without antibiotic selection. Biotechnol Prog. 2000 Jan-Feb;16(1):17-25 Nemir M, Bhattacharyya D, Li X, Singh K, Mukherjee AB, Mukherjee BB. Targeted inhibition of osteopontin expression in the mammary gland causes abnormal morphogenesis and lactation deficiency. J Biol Chem. 2000 Jan 14;275(2):969-76.Zheng F, Kundu GC, Zhang Z, Ward J, DeMayo F, Mukherjee AB.Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice. Nat Med.5: 1999 1018-25;Loss of transformed phenotype in cancer cells by overexpression of the uteroglobin gene. Proc Natl Acad Sci1999 Mar 30;96(7):3963-8; Zhang Z, Mandal AK, Wang N, Keck CL, Zimonjic DB, Popescu NC, Mukherjee AB. (1999)Palmitoyl-protein thioesterase gene expression in the developing mouse brain and retina: implications for early loss of vision in infantile neuronal ceroid lipofuscinosis.Gene. 231(1-2):203-11.

关于发育遗传学的部分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复杂遗传疾病的分子机制，以开发新颖的治疗方法。朝向这些目标，本节的实验室研究集中在理解主要是两个基因的调节和生理功能上：（1）子宫球蛋白（UG），也称为Clara细胞10 kDa蛋白（CC10）和（2）palmityloyl-plotel-protein thioesterase-1（PPT1）。 PPT1基因中的灭活突变是婴儿神经蛋白酶脂肪促脂肪促脂肪促（含）的遗传基础，也被称为婴儿the病。含有毁灭性的神经退行性储存疾病。为此没有有效的治疗。 UG敲除小鼠会产生免疫球蛋白A（IgA） - 肾上腺病，这是一种原发性肾肾小球疾病，通常导致肾衰竭。这种疾病也没有有效的治疗方法。含有的实验室调查导致了目前正在进行的基准对床位临床试验。最近，使用PPT1-KNOCKOUT（PPT1-KO）小鼠，它概括了几乎所有的临床和病理特征，我们首次发现TPPT1缺乏效率会导致内质网应激（ER）应力（ER）应力（ER）应力（ER）应力，从而激活了已溶出的蛋白质反应培养蛋白质反应培养蛋白质，从而培养了肾上腺的死亡。我们的实验结果并非一方面，可以洞悉含有神经变性的复杂机制，但也确定了为这种统一致命疾病开发有理理性和新型治疗方法的一些潜在靶标。 **出版物：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。鼠胰腺磷脂酶A的分子表征（2）。 DNA细胞生物。 2001年3月; 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; Zhang Z，Mandal AK，Mital A，Popescu N，Zimonjic D，Moser A，Moser H，Mukherjee AB。人酸神经酶基因：法伯疾病中的新突变。 mol Genet Metab。 2000年8月； 70（4）：301-9。 Yuan CJ，Mandal AK，Zhang Z，Mukherjee AB。环氧酶-2基因表达的转录调节：非甾体类抗炎药的新作用。癌症。 2000年2月15日； 60（4）：1084-91。 Zheng F，Kundu G，Zhang Z，Mukherjee AB，Ward J，DemayoF。在两种不同的子宫脂蛋白缺乏的小鼠模型中相同的肾小球病。是J肾脏Dis。 2000年2月; 35（2）：362-3。 Mantile G，Fuchs C，Cordella-Miele E，Peri A，Mukherjee AB，Miele L稳定，可溶性，二聚体，二硫键键合的蛋白药物的长期细菌产生，无需抗生素选择。生物技术训练。 2000 Jan-Feb; 16（1）：17-25 Nemir M，Bhattacharyya D，Li X，Singh K，Mukherjee AB，Mukherjee BB。在乳腺中靶向抑制骨桥蛋白表达会导致异常形态发生和泌乳缺乏。 J Biol Chem。 2000年1月14日； 275（2）：969-76.Zheng F，Kundu GC，Zhang Z，Ward J，Demayo F，Mukherjee AB.Uteroglobin。 Nat Med.5：1999 1018-25;通过子宫球蛋白基因的过表达，癌细胞中转化的表型丧失。 Proc Natl Acad Sci1999 3月30日； 96（7）：3963-8; Zhang Z，Mandal AK，Wang N，Keck CL，Zimonjic DB，Popescu NC，Mukherjee AB。 （1999）发育中的小鼠脑和视网膜中棕榈酰蛋白硫酯酶基因的表达：对婴儿神经元蛋白脂肪促肌肉菌病的早期视力丧失的影响。 231（1-2）：203-11。