Heritable Disorders Of Lipid Metabolism

脂质代谢遗传性疾病

• 批准号: 6671855
• 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/6671855
• 关键词: IgA nephropathy; apoptosis; biological signal transduction; chemokine; disease /disorder model; extracellular matrix; gene mutation; gene targeting; genetic disorder; globulins; human tissue; laboratory mouse; lipid metabolism; mammary gland; neuronal ceroid lipofuscinosis; phospholipase A2

The Section on Developmental Genetics conducts both basic and clinical investigations to understand molecular mechanisms of hereditary neurodegenerative and inflammatory/autoimmune diseases and to develop novel approaches for the treatment of these diseases. During the past year we have: (A) uncovered a novel innate homeostatic mechanism that counteracts airway inflammation and protects against allergic asthma. In this scenario, uteroglobin (UG) is an essential component that counteracts inadvertent activation of allergen-induced inflammatory response in this vital organ and prevents allergic asthma; (B) demonstrated that uteroglobin-deficient mice exhibit an altered pulmonary eosinophilic inflammation. Our results provided the first in vivo evidence that UG plays a role in the modulation of pulmonary allergic inflammation; (C) delineated the molecular mechanism of inhibition of phospholipase A2 activity by UG. By site-specific mutation, we demonstrated that Lys 43 Glu, Asp 46 Lys or a combination of the two mutations in the full-length, recombinant human UG (rhUG) abrogates its sPLA2-inhibitory activity; (D) under a collaborative research and development agreement (CRADA) a Phase I clinical study of recombinant human UG for prevention of bronchopulmonary dysplasia in premature infants with respiratory distress syndrome was successfully completed. Clinical development of rhUG for prevention of neonatal BPD with a Phase II trial, as well as continuing the pre-clinical work for the application of rhUG in ARDS and asthma will be carried out in the coming year; (E) initiated pilot study to determine whether Cystagon is beneficial for infantile neuronal ceroid lipofuscinosis (INCL) patients.This study will continue until we recruit 5 patients, as approved and final analyses will be made when all data are available. Publications: 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(4):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. No abstract available. Kundu GC, Zhang Z, Mantile-Selvaggi G, Mandal A, Yuan CJ, Mukherjee AB. Uteroglobin binding proteins: regulation of cellular motility and invasion in normal and cancer cells. Ann N Y Acad Sci. 2000;923:234-48. 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. Review. Pattabiraman N, Matthews JH, Ward KB, Mantile-Selvaggi G, Miele L, Mukherjee AB. Crystal structure analysis of recombinant human uteroglobin and molecular modeling of ligand binding. Ann N Y Acad Sci. 2000;923:113-27. 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.

关于发育遗传学的部分进行了基本和临床研究，以了解遗传神经退行性和炎症/自身免疫性疾病的分子机制，并开发用于治疗这些疾病的新方法。在过去的一年中，我们有：（a）发现一种新型的先天体内稳态机制，该机制抵消了气道炎症并预防过敏性哮喘。在这种情况下，子宫球蛋白（UG）是必不可少的组成部分，可抵消过敏原诱导的这种重要器官中炎症反应的无意激活，并防止过敏性哮喘。 （b）证明子宫蛋白缺乏小鼠表现出改变的肺嗜酸性炎症。我们的结果提供了第一个体内证据，表明UG在调节肺部过敏性炎症中起作用。 （c）描绘了通过UG抑制磷脂酶A2活性的分子机制。通过位点特异性突变，我们证明了LYS 43 GLU，ASP 46 LYS或全长重组人UG（Rhug）中两个突变的组合消除了其SPLA2抑制活性。 （d）在一项协作研究与发展协议（CRADA）下，在早产儿呼吸遇险综合征的早产儿中，对预防支气管肺发育不良的重组人UG进行了I期临床研究。通过II期试验预防新生儿BPD的Rhug的临床开发，并继续在来年进行临床前的工作，以在ARDS和哮喘中应用Rhug； （e）启动试点研究，以确定囊肿是否对婴儿神经元蛋白脂肪促脂肪促脂肪促（含）患者有益。这项研究将继续持续到我们招募5名患者，如所有数据可用时，将进行批准和最终分析。出版物：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（4）：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。没有抽象可用。 Kundu GC，Zhang Z，Mantile-Selvaggi G，Mandal A，Yuan CJ，Mukherjee AB。子宫蛋白结合蛋白：正常和癌细胞中细胞运动和侵袭的调节。 Ann n y Acad Sci。 2000; 923：234-48。 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。审查。 Pattabiraman N，Matthews JH，Ward KB，Mantile-Selvaggi G，Miele L，Mukherjee AB。重组人子宫球蛋白的晶体结构分析和配体结合的分子建模。 Ann n y Acad Sci。 2000; 923：113-27。 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。