Targeting M. Leprae survival strategies in the PNS

针对 PNS 中的麻风分枝杆菌生存策略

• 批准号: 7153553
• 负责人: ANURA RAMBUKKANA
• 金额: $ 37.61万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7153553
• 关键词: Accounting; Antibodies; Apoptosis; Apoptotic; Biology; Cell Cycle; Cell Cycle Progression; Cell Cycle Proteins; Cell Proliferation; Cell Survival; Cell physiology; Cities; Condition; Cyclin-Dependent Kinases; Cyclins; Deformity; Degenerative Disorder; Demyelinations; Disease Progression; Enzymes; Fibroblast Growth Factor; Genes; Genome; Growth; Growth Factor; Growth Factor Receptors; Hand; Health; Human; Immunoblotting; In Vitro; Infection; Insulin; Insulin-Like Growth Factor I; Lead; Leprosy; Link; Metabolic; Metabolic Pathway; Microarray Analysis; Mitochondria; Modeling; Mycobacterium leprae; Nerve; Nerve Growth Factors; Nerve Regeneration; Nervous System Trauma; Neuroglia; Neurons; Numbers; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Phenotype; Prevention; Property; Pseudogenes; Regulation; Respiratory Chain; Respiratory physiology; Reverse Transcriptase Polymerase Chain Reaction; Role; Schwann Cells; Secure; Signal Pathway; Signal Transduction; Signaling Molecule; Time; Transcriptional Activation; Up-Regulation; Week; cdc Genes; cell growth; day; disability; glucose metabolism; in vivo; inhibitor/antagonist; insight; neurotrophic factor; neurotropic; novel; novel therapeutics; pathogen; receptor

Leprosy remains an important global health problem, and represents a classical example of infectious neuro- degenerative diseases of the peripheral nervous syetm (PNS). Mycobacterium leprae infection of Schwann cell, the glial cell of the PNS, is the primary cause for the nerve damage in leprosy. We have recently shown that the non-myelinating Schwann cell, but not the myelinated Schwann cell, preferentially harbors M. leprae, and thus serves as the intracellular niche for persistent infection. Because M. leprae is an obligate intra- cellular pathogen with the longest doubling time and limited number of genes in its genome, the establishment of productive infection within non-myelinated Schwann cells is the key for bacterial survival. However, the mechanisms of M. leprae survival within Schwann cells are unknown. Targeting of M. leprae survival strategies will provide the rational to develop new therapeutics to combat the neurological injury and disease progression. To study these aspects, we used primary human Schwann cells (isolated and purified from human peripheral nerves) as a model, since they phenotypically resemble non-myelinated Schwann cells in vivo. Intracellular M. leprae in vitro maintain viability for several weeks without causing any apoptosis or cytopathic effect to Schwann cells. Microarray analysis using Affimatrix human GeneChips with cRNA prepared from primary human Schwann cells infected with viable M. leprae for 30 days, we showed that the majority of differentially expressed Schwann cells genes are (i) enzymes that regulate metabolic and respiratory functions, (ii) cell cycle regulators/inhibitors, (iii) growth/neurotropic factors, (iv) growth factor receptors and (v) associated transcriptional and signaling molecules. Therefore, we propose that once infected, M. leprae effectively use Schwann cell machinery in one hand to maintain the bacterial viability and the other hand to secure the intracellular niche for long-term bacterial survival by regulating Schwann cell growth. To study these, we will study the following: (1) M. leprae regulation of Schwann cell metabolic/ catabolic functions, (2) Regulation of human Schwann cell cycle by M. leprae, and (3) M. leprae-induced growth/neurotropic factors and their effects on Schwann cell signaling, growth and functions. These studies should provide novel insight into the persistent M. leprae infection in the PNS, nerve damage in leprosy patients, and the basic biology of glial cells. city, state)

麻风病仍然是一个重要的全球健康问题，是传染性神经系统疾病的典型例子。 周围神经系统退行性疾病（PNS）。许旺氏麻风分枝杆菌感染 细胞（PNS的胶质细胞）是麻风病神经损伤的主要原因。我们最近的研究表明 无髓鞘的雪旺氏细胞，而不是有髓鞘的雪旺氏细胞，优先窝藏M。麻风病， 因此作为持续感染的细胞内小生境。因为M.麻风病是一种 在其基因组中具有最长倍增时间和有限数量基因的细胞病原体， 在无髓鞘雪旺细胞内建立生产性感染是细菌存活的关键。 然而，M.麻风病人在雪旺氏细胞中存活率是未知的。M的目标。麻风 生存策略将为开发新的治疗方法以对抗神经损伤提供合理性， 疾病进展。为了研究这些方面，我们使用原代人雪旺细胞（分离和纯化的 来自人外周神经）作为模型，因为它们在表型上类似于无髓鞘的Schwann 体内细胞胞内M.麻风在体外维持存活数周而不引起任何细胞凋亡 或对雪旺细胞的致细胞病变作用。使用Affimatrix人类基因芯片与cRNA的微阵列分析 由感染活M.麻风病30天，我们发现， 大多数差异表达的雪旺细胞基因是（i）调节代谢的酶， 呼吸功能，（ii）细胞周期调节剂/抑制剂，（iii）生长/神经营养因子，（iv）生长因子 受体和（v）相关的转录和信号分子。因此，我们建议，一旦 感染M.麻风病人一方面有效地利用许旺细胞机制来维持细菌活力， 另一方面通过调节雪旺细胞来确保细菌长期存活的细胞内生态位 增长为了研究这些现象，我们将研究以下几个方面：（1）M.麻风对雪旺细胞代谢调节/ （2）M.（3）M.麻风诱发的 生长/神经营养因子及其对雪旺细胞信号传导、生长和功能的影响。这些研究 应该提供新的见解持久的M。PNS中的麻风感染，麻风的神经损害 病人和神经胶质细胞的基础生物学。 城市，州）