（5.13-5.26/2012）
恒峰g22国际集团:陶国新 

　　重要内容：首例针对端粒酶的基因医治使老鼠寿命健全耽搁24%；维生素K2可能援手产能不及的线粒体维持正常的ATP产量；持续压造蛋白质翻译造成普里昂蛋白引起的神经变性；皮肤附件的生理再生及其对再生医学生理学的意思；进行糖酵解的少突胶质细胞守护髓鞘和轴突的持久齐全性；基因疗法医治失聪的潜力和局限。

　　焦点动态：首例针对端粒酶的基因医治使老鼠寿命健全耽搁24%

1. 首例针对端粒酶的基因医治使老鼠寿命健全耽搁24%
【动态】 西班牙科学家最近的钻研成功的诱导细胞表白端粒酶
，调慢生物钟
，在概想上为有效的提高健全寿命的可行且安全的步骤提供了证据。 之前有好多钻研已经批注通过调节特定基因可能耽搁蕴含哺乳动物在内的很多物种的均匀寿命
，但迄今为止
，这些步骤都必要从胚胎阶段就永远性的扭转动物的基因
，这在人类是不成行的。而最近西班牙科学家的钻研批注对成大哥鼠执行一次基因医治可能耽搁其寿命。他们使用了以前从没用于抗衰老的一种基因医治战术
，并发此刻老鼠上是安全有效的。他们遴选了一种不复造非致病的去除自身基因的病毒作为载体别离向1年大的老鼠和2年大的老鼠体内送入可在较长功夫内表白的老鼠端粒酶逆转录酶（TERT）基因
，别离耽搁老鼠均匀寿命达24%和13%
，并且显著改善了健全情况
，延长了骨质疏松、胰岛素抗性等衰老有关疾病
，同时没有提高患癌风险。
【点评】 只管上述通过在成年和老迈哥鼠体内引入端粒酶基因的步骤至少在短期内可能无法作为抗衰老的疗法利用于人类
，这一思路可能为组织内端粒异常缩短的疾病提供了一种可供选择的医治规划。

【参考论文】 EMBO Molecular Medicine, 2012 (in press) DOI: 10.1002/emmm.201200245 
Telomerase gene therapy in adult and old mice delays ageing and increases longevity without increasing cancer
Bruno Bernardes de Jesus, Elsa Vera, Kerstin Schneeberger, et al.
A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) andold (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase-treated mice, both at 1-year and at 2-year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof-of-principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase-based treatment, and demonstrate the feasibility of anti-aging gene therapy.

2. 维生素K2可能援手产能不及的线粒体维持正常的ATP产量
【动态】比利时和美国科学家的一项合作钻研最近发现维生素K2可能援救基因突变造成的线粒体职能阻碍
，为由于这种线粒体职能阻碍造成的帕金森症患者带来了但愿。线粒体作为能量工厂提供细胞正常运行所需能量。线粒体通过转运电子产能
，而在帕金森患者这一职能被粉碎
，导致线粒体无法产出足够能量。只管正确病因还不明显
，最近几年
，已发现诸如PINK1 和 Parkin 基因突变存在于帕金森患者体内
，二者城市引起线粒体职能减弱。比利时和美国科学家用PINK1 或 Parkin 基因突变的果蝇作为模式生物
，发现两种果蝇都失去了飞行能力。进一步的查抄发现这些果蝇体内的线粒体就像帕金森患者的一样有职能缺点
，产能削减。当喂给这些果蝇维生素K2后
，它们线粒体的能量出产复原了
，提高了飞行能力。钻研也证明这种能量出产复原是由于维生素K2作为电子转运载体推进了线粒体内的电子转运。
【点评】维生素K2作为线粒体内电子载体
，可能援手因基因突变造成产能不及的线粒体维持正常的ATP出产量
，也许将来有但愿为帕金森患者提供新的医治规划。

【参考论文】
Science, 2012; DOI:10.1126/science.1218632
Vitamin K2 Is a Mitochondrial Electron Carrier That Rescues Pink1 Deficiency
M. Vos, G. Esposito, J. N. Edirisinghe, et al.
Human UBIAD1 localizes to mitochondria and converts vitamin K1 to vitamin K2. Vitamin K2 is best known as a cofactor in blood coagulation, but in bacteria it is a membrane-bound electron carrier. Whether vitamin K2 exerts a similar carrier function in eukaryotic cells is unknown. We identified Drosophila UBIAD1/Heix as a modifier of pink1, a gene mutated in Parkinson’s disease that affects mitochondrial function. Here, we found that vitamin K2 was necessary and sufficient to transfer electrons in Drosophila mitochondria. Heix mutants showed severe mitochondrial defects that were rescued by vitamin K2, and, similar to ubiquinone, vitamin K2transferred electrons in Drosophila mitochondria, resulting in more efficient adenosine triphosphate (ATP) production. Thus, mitochondrial dysfunction was rescued by vitamin K2 that serves as a mitochondrial electron carrier, helping to maintain normal ATP production.

3. 持续压造蛋白质翻译造成普里昂蛋白引起的神经变性
【动态】目前对于神经变性疾病中神经细胞的殒命原因还很不明显
，很多此类疾病
，像老年痴呆、帕金森症和疯牛病都与谬误折叠的疾病特异蛋白的堆集有关联。这些谬误折叠的蛋白水平的上起用起细胞的；ば苑从-蛋白去折叠。这一反映蹊径的影响之一是临时终止蛋白质翻译。而英国科学家的最新钻研发现阮病毒复造过程中的普里昂蛋白的堆会议悠久压造整体的蛋白质合成
，使得阮病毒习染的老鼠神经突触故障、神经元迷失
，而推进复原这些老鼠海马区的蛋白质翻译可能；ど窬。鉴于蛋白谬误折叠和细胞蛋白去折叠的；ば苑从称毡榇嬖谟敫骼嗌窬湫约膊≈
，他们的了局揭示了调节像翻译节造这样的共同的生化蹊径而非疾病特异性蹊径
，或许可能发现新的疗法预防神经突触故障和神经元迷失。

【点评】 该钻研显示了一种萌芽状态的思路转变即从针对疾病治病到针对换节身段的正常职能治病。也就是说这项钻研的钻研人员起头意识到通过复原机体的正常职能来达到去除某些特定疾病也许是一种更好的医学思路。

【参考论文】
Nature, 2012; DOI:10.1038/nature11058
Sustained translational repression by eIF2α-P mediates prion neurodegeneration
Julie A. Moreno, Helois Radford, Diego Peretti, et al. 
The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer’s, Parkinson’s and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2α-P levels are seen in patients with Alzheimer’s, Parkinson’s and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2α-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2α-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2α-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation, increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.

4. 皮肤附件的生理再生及其对再生医学生理学的意思
【动态】最近一篇美国英国台湾科学家合作颁发的综述文章会商了皮肤附件的生理再生及其对再生医学生理学的意思。只管再生医学还是个相对比力新的概想
，各人都知路动物可能通过正常的生理再生过程定期更生头发和羽毛。该文章审查了数十篇关于正常生理再生—动物平生拥有的再成长而非对危险的反映—的论文。这种再生在动物成长的分歧阶段当令地发生（好比鸟类的换羽毛
，幼男孩的细软面部毛发在青春期被髯毛代替）。这些变动是对像毛囊自身的生理这类内涵成分或环境等表在成分的响应
，但这些正常变动的内涵机造还不明显。毛囊中的干细胞推进毛发和羽毛的再生
，但钻研人员此刻还不知路若何疏导这些细胞形成皮肤附件的正常状态尺寸和定位
，也不知路若何让受伤后形成疤痕的人体皮肤再长出毛发。这些未知的知识很可能藏有有价值的线索疏导我们相识若何伤后再生更复杂更有价值的结构如手指和脚趾。

【点评】 该综述总结了目前再生生物学的发展和局限
，也等待更深刻的钻研正常的再生生理机造可能援手在机体受伤后再生出比毛发更复杂的生理结构。他们想到的这些事件在人体再生复原科学的领域里都已成为现实了
，只管更深刻的再朝气造还必要持续钻研。

【参考论文】
Physiology, April 2012 27:61-72 DOI: 10.1152/physiol.00028.2011
Physiological Regeneration of Skin Appendages and Implications for Regenerative Medicine Physiology
Cheng-Ming Chuong, Valerie A. Randall, Randall B. Widelitz, et al.
The concept of regenerative medicine is relatively new, but animals are well known to remake their hair and feathers regularly by normal regenerative physiological processes. Here, we focus on 1) how extrafollicular environments can regulate hair and feather stem cell activities and 2) how different configurations of stem cells can shape organ forms in different body regions to fulfill changing physiological needs.

5. 进行糖酵解的少突胶质细胞守护髓鞘和轴突的持久齐全性
【动态】人脑中约1000亿的神经细胞支持恒峰g22思虑感触和行动。这些细胞长的神经纤维即轴突将电信号传递到大脑和身段的远端。这种通讯必要大量的被以为是来自糖的能量。轴突与胶质细胞缜密相连
，后者用不导电的髓鞘包绕轴突并支持轴突的持久职能。最近一个国际科研团队发现了一种可能的机造
，这些脑中的胶质细胞借以支持轴突并维持轴突的持久生涯。少突胶质细胞是中枢神经系统中一组高度特异性的胶质细胞
，掌管形成富含脂肪的包绕轴突的髓鞘绝缘层
，但髓鞘的职能不止是绝缘
，它能增长轴突的信号传递速度
，削减能量亏损。髓鞘的极端重要性在因绝缘层职能缺点导致的疾病如多发性硬化中得以体现。而少突胶质细胞的职能也远不止提供髓鞘层。该团队发现健全的胶质细胞是轴突持久职能和存活的无关髓鞘天生的必须成分。胶质细胞参加了神经纤维的能量补给
，健全的成熟胶质细胞重要通过糖酵解产生能量
，其优势在于糖酵解过程中的代谢产品能够用于髓鞘合成
，并且在少突胶质细胞中天生的乳酸可能传给轴突用于轴突自身线粒体的能量出产。 
【点评】 该钻研发现的胶质细胞和轴突在生理上的相互共同和协调证明作为机体职能的正常阐扬必须整体的共同和协调
，分歧的结构在分歧的生理前提下各自拥有维持性命职能正常的重要作用。

【参考论文】
Nature, 2012; DOI: 10.1038/nature11007
Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity
Ursula Fünfschilling, Lotti M. Supplie, Don Mahad, et al. 
Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon–glia interactions by generating conditional Cox10(protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome coxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon–glia metabolic coupling serves a physiological function.

6. 基因疗法医治失聪的潜力和局限
【动态】美国科学家最近发此刻年幼老鼠的耳蜗引入Atoh1基因（毛细胞分化因子）可能诱导成长更多的听觉毛细胞。这些新生的毛细胞像正常毛细胞一样产生电信号并与神经细胞相连
，但是在老鼠两周大以来青春期之前引入Atoh1基因险些没有作用。这预示着在成年人利用类似的疗法也不会有效。

【点评】在基因刷新的动物模型身上发现的景象并不用然反映在正常动物身上
，更不用说与人体的反映有多大有关性。并且从婴幼儿动物进行的基因过问在处置成年动物疾病时也不成行
，并且还存在基因过问后的其他不成意料的了局。

【参考论文】
Journal of Neuroscience, 2012; 32 (19): 6699 DOI:10.1523/JNEUROSCI.5420-11.2012
Atoh1 Directs the Formation of Sensory Mosaics and Induces Cell Proliferation in the Postnatal Mammalian Cochlea In Vivo
M. C. Kelly, Q. Chang, A. Pan, X. Lin, P. Chen.

Hearing impairment due to the loss of sensory hair cells is permanent in humans. Considerable interest targets the hair cell differentiation factor Atoh1 as a potential tool with which to promote hair cell regeneration. We generated a novel mouse model to direct the expression of Atoh1 in a spatially and temporally specific manner in the postnatal mammalian cochlea to determine the competency of various types of cochlear epithelial cells for hair cell differentiation. Atoh1 can generate cells in young animals with morphological, molecular, and physiological properties reminiscent of hair cells. This competency is cell type specific and progressively restricted with age. Significantly, Atoh1 induces ectopic sensory patches through Notch signaling to form a cellular mosaic similar to the endogenous sensory epithelia and expansion of the sensory mosaic through the conversion of supporting cells and nonautonomous supporting cell production. Furthermore, Atoh1 also activates proliferation within the normally postmitotic cochlear epithelium. These results provide insight into the potential and limitations of Atoh1-mediated hair cell regeneration.