企业邮箱
世界性命科学前沿动态周报(二)
（03.29--04.04 / 2010）
俄罗斯贵宾会集团国际集团:陶国新
本周的进展大多是关于基因医治方面的。 其中发现节造涡虫再生能力“总开关” 的报路比力有意思。对于我们相识动物的再生有很好的启迪。另表两篇有关多巴胺D2受体的文章在基因层面上看到了其对吃垃圾食品和睡眠的影响 ，对于养生保健或许有所援手。其余是有关基因疗法的一些进展和基因运载的新技术 ，基因与衰老、免疫的关系等。
1. 发现节造涡虫再生能力“总开关”
【提要】
一种名接装涡虫”的扁形虫即便被切成百段 ，一两周后每段城市再生出齐全的涡虫。涡虫这种超强再生能力一向是科学家感兴致的钻研课题。近年来对涡虫最感兴致的是从事干细胞钻研的科学家 ，由于钻研发现 ，涡虫再生的奥秘在于其体内有一种散布全身的全能干细胞 ，其分化能力类似人类胚胎干细胞。有所分歧的是 ，涡虫这种干细胞能在职何功夫分化成其他任何种类的细胞。涡虫的身段被堵截后 ，它体内散布在遍地的这些干细胞能转造成神经、肌肉、肠等各类组织细胞 ，沉新长出那些失去的部门。
德国科学家最近发现了一种对涡虫的再生能力有关键调节作用的蛋白质。他们但愿这一发现有助于人类干细胞钻研。 德国马克斯•普朗克分子生物钻研所科学家用核糖核酸（RNA）滋扰抑造基因表白的方式抑造了涡虫体内蛋白质“Smed—SmB”的合成 ，了局发现这导致涡虫体内的全能干细胞均不能割裂 ，涡虫因而失去了再生能力。参加钻研的科学家说 ，这相当于发现了影响涡虫干细胞割裂的“总开关” ，这一发现可能有助于人们深刻相识组织缺损建复的机理。由于涡虫细胞中四分之三的基因与人类基因类似 ，科学家还但愿他们的钻研成就有助于人类干细胞钻研。新华网 颁布功夫：2010-4-1 16:12:39
【点评】
若是能证实关关其它基因涡虫依然能再生的话 ，那么Smed-Smb蛋白就很可能是个涡虫全效成长因子。若是能在哺乳动物体内发现类似职能的蛋白 ，那将是极度惊人的�；蛐矶砺匏构蟊龌峒旁偕镏世镉欣嗨浦澳艿某煞郑�？ 结合上期的“发现哺乳动物节造再生能力基因”关关p21 ，开启再生的报路 ，一对掌控再生能力的基因开关就出现了: p21抑造再生 ，表白Smed-Smb类似蛋白的基因推进再生。 而发展有效的 RNAi 技术来按必要关关对应基因能够达到推进或抑造再生的主张。不外看起来离这个了局还很远。但是对于进一步相识动物的再朝气理是有援手的。
【原文摘录】
doi: 10.1242/dev.042564 April 1, 2010 Development 137,1055-1065.
Smed-SmB, a member of the LSm protein superfamily, is essential for chromatoid body organization and planarian stem cell proliferation
Enrique Fernandéz-Taboada1, Sören Moritz2, Dagmar Zeuschner2, Martin Stehling2, Hans R. Schöler2,3, Emili Saló1,* and Luca Gentile2,*
Planarians are an ideal model system to study in vivo the dynamics of adult pluripotent stem cells. However, our knowledge of the factors necessary for regulating the ‘stemness’ of the neoblasts, the adult stem cells of planarians, is sparse. Here, we report on the characterization of the first planarian member of the LSm protein superfamily, Smed-SmB, which is expressed in stem cells and neurons in Schmidtea mediterranea. LSm proteins are highly conserved key players of the splicing machinery. Our study shows that Smed-SmB protein, which is localized in the nucleus and the chromatoid body of stem cells, is required to safeguard the proliferative ability of the neoblasts. The chromatoid body, a cytoplasmatic ribonucleoprotein complex, is an essential regulator of the RNA metabolism required for the maintenance of metazoan germ cells. However, planarian neoblasts and neurons also rely on its functions. Remarkably, Smed-SmB dsRNA-mediated knockdown results in a rapid loss of organization of the chromatoid body, an impairment of the ability to post-transcriptionally process the transcripts of Smed-CycB, and a severe proliferative failure of the neoblasts. This chain of events leads to a quick depletion of the neoblast pool, resulting in a lethal phenotype for both regenerating and intact animals. In summary, our results suggest that Smed-SmB is an essential component of the chromatoid body, crucial to ensure a proper RNA metabolism and essential for stem cell proliferation.
2. 垃圾食品成瘾症或的确存在
【提要】
美国最新钻研显示 ，肥胖人群无法回绝美食引诱的诠释可能并不是给自己找借口 ，垃圾食品成瘾症似乎的确存在。 这一发现是通过老鼠钻研得出的。在钻研人员无限度地为老鼠提供熏肉、磅饼、糖块以及其它垃圾食品等高热量食品之后 ，老鼠体沉急剧增长。随着身段越来越胖 ，吃器材造成一种胁迫 ，即便这么做双脚会遭逢电击 ，它们也不愿意放下爪子 ，持续享受美食。相比之下 ，享受健全食品的老鼠并未增长太多体沉 ，在意识到吃的过多会遭到电击之后 ，它们便终场进食。钻研人员指出 ，更令人感应吃惊的是 ，在拿走肥胖老鼠的垃圾食品并换上健全食品之后 ，这些家伙竟然选择绝食。在长达两周功夫里 ，它们回绝吃任何器材。钻研人员尚无法确定钻研了局是否也合用于人类。
在对胖老鼠的大脑进行分析时 ，钻研人员发现多巴胺D2受体削减。凭据此前进行的钻研 ，这种受体与可卡因和海洛因成瘾有关�？夏崴担骸岸抉囊桓霰曛揪褪堑贾麓竽越鄙拖低彻ぷ骰觳涠�。”在人为抑造其他老鼠脑中的这种受体之后 ，这些老鼠也起头情不自禁地转向垃圾食品。波士顿大学医学院成瘾症尝试室助理教授皮埃特罗•科特纳暗示 ，不休堆积的脂肪中的一些物质也会扭转大脑的奖赏阈限 ，进而形成一个恶性循环——只有吃得更多 ，能力获得满足感�？铺啬伤担骸盎氐秸Ｗ刺奈ㄒ环绞骄褪浅志媒谑场⑾骷跆宄镣辈辉俪岳称�。”他与同事此前进行的钻研显示 ，让老鼠脱节高热量食品可能导致大脑出现与戒毒和戒酒类似的变动。
【点评】
多巴胺有关的大脑奖赏系统工作机造由于成瘾行为而产生扭转 ，多巴胺D2受体削减。该文老鼠尝试显示 ，此刻这类成瘾行为行列里很可能又参与了吃垃圾食品。再生养生的健全食谱排除了这种成瘾行为 ，预防大脑奖赏系统工作机造的异常扭转 ，维持健全的大脑职能。结合下篇的多巴胺D2受体剔除幼鼠的睡眠钻研 ，能够揣摩 ，垃圾食品成瘾的人很可能的会越吃越多 ，越睡越多 ，越长越胖 ，任期发展下去 ，最后身段各器官会不胜沉负 ，出现各类病理情况甚至衰竭�？杉蒲б扯越∪嵌嗝吹某烈�。
【原文摘录】
Nature Neuroscience | Article
Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats
Published online 28 March 2010 Paul M Johnson & Paul J Kenny
We found that development of obesity was coupled with emergence of a progressively worsening deficit in neural reward responses. Similar changes in reward homeostasis induced by cocaine or heroin are considered to be crucial in triggering the transition from casual to compulsive drug-taking. Accordingly, we detected compulsive-like feeding behavior in obese but not lean rats, measured as palatable food consumption that was resistant to disruption by an aversive conditioned stimulus. Striatal dopamine D2 receptors (D2Rs) were downregulated in obese rats, as has been reported in humans addicted to drugs. Moreover, lentivirus-mediated knockdown of striatal D2Rs rapidly accelerated the development of addiction-like reward deficits and the onset of compulsive-like food seeking in rats with extended access to palatable high-fat food. These data demonstrate that overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating. Common hedonic mechanisms may therefore underlie obesity and drug addiction.
3. “多巴胺D2受体”钻研为医治“第一晚效应”提供新思路
【提要】
医学上把一些人换床后无法入睡的景象称为“第一晚效应”。资料显示 ，随着工业化过程的加快 ，社会竞争、工作压力、不良夜生涯习惯及人丁老龄化等原因 ，全球三分之一的人存在睡眠问题 ，其中不少人因时时出差不能在习惯的床上睡眠或入睡前感情扭转、心灵亢奋或严重而难以入眠 ，深陷“第一晚效应”的疾苦之中不能自拔 ，严沉影响到次日工作效能和身段健全。复旦大学医学神经生物学国度沉点尝试室黄志力课题组钻研人员曲卫敏副教授、徐昕红博士等使用高度自动化睡眠醒觉解析系统 ，纪录已经基因剔除“多巴胺D2受体”幼鼠的睡眠过程 ，并结合药理学等伎俩 ，从基因到行为解析了多巴胺D2受体在睡眠醒觉调控中的作用。了局发现 ，与正常幼鼠（野生型幼鼠）相比 ，剔除了多巴胺D2受体的幼鼠 ，活动期维持醒觉难题 ，睡眠量增长。 为仿照人在新环境下如出差住宿等 ，出现换床后失眠景象 ，即“第一晚效应” ，钻研人员更换动物居住环境 ，调查幼鼠在新环境中的睡眠行为。了局显示 ，多巴胺D2受体正常的幼鼠面对新环境刺激 ，极为不习惯、入睡难题 ，而剔除了多巴胺D2受体的幼鼠则“安枕无忧” ，迅速入睡。
【点评】
多巴胺D2受体删除的老鼠尝试中不出现”第一晚效应”, 在新环境中能迅速入睡 ，且睡眠量增长。 这个景象是否与生物钟有关 ，能否在改善睡眠上有利用价值 ，值得钻研一下 ，看是否可能用在生物钟饮食疗法上。不外必要把稳的是 ，通过基因敲除技术钻研的结论只是单个（或某几个）基因的作用 ，无法思考或排除整体的调控在其中的影响 ，因而结论往往不是那么极度确定的。
【原文摘录】
The Journal of Neuroscience, March 24, 2010, 30(12):4382-4389; doi:10.1523
Essential Role of Dopamine D2 Receptor in the Maintenance of Wakefulness, But Not in Homeostatic Regulation of Sleep, in Mice
Wei-Min Qu,1 Xin-Hong Xu,1 Ming-Ming Yan,1 Yi-Qun Wang,1 Yoshihiro Urade,2 and Zhi-Li Huang1
Dopamine (DA) and its D2 receptor (R) are involved in cognition, reward processing, and drug addiction. However, their roles in sleep–wake regulation remain unclear. Herein we investigated the role of D2R in sleep–wake regulation by using D2R knock-out (KO) mice and pharmacological manipulation. Compared with WT mice, D2R KO mice exhibited a significant decrease in wakefulness, with a concomitant increase in non-rapid eye movement (non-REM, NREM) and REM sleep and a drastic decrease in the low-frequency (0.75–2 Hz) electroencephalogram delta power of NREM sleep, especially during the first 4 h after lights off. The KO mice had decreased mean episode duration and increased episode numbers of wake and NREM sleep, many stage transitions between wakefulness and NREM sleep during the dark period, suggesting the instability of the wake stage in these D2R KO mice. When the KO mice were subjected to a cage change or an intraperitoneal saline injection, the latency to sleep in the KO mice decreased to half of the level for WT mice. The D2R antagonist raclopride mimicked these effects in WT mice. When GBR12909, a dopamine transport inhibitor, was administered intraperitoneally, it induced wakefulness in WT mice in a dose-dependent manner, but its arousal effect was attenuated to one-third in the D2R KO mice. However, these 2 genotypes showed an identical response in terms of sleep rebound after 2, 4, and 6 h of sleep deprivation. These results indicate that D2R plays an essential role in the maintenance of wakefulness, but not in homeostatic regulation of NREM sleep.
4. 番茄基因加抗艾滋药物的新基因疗法医治癌症
【提要】
瑞典钻研人员最新发现 ，一种番茄基因与药物组合后能粉碎癌细胞 ，这一发现将有助于用基因疗法医治癌症。瑞典隆德大学钻研人员日前颁发公报说 ，这种番茄基因在援手成立和建复番茄基因组方面“非�；钤尽� ，但它自身并不及以粉碎癌细胞。在先后测试了分歧药物后 ，钻研人员最终发现 ，这种番茄基因与抗艾滋病药物AZT组合后 ，能更有效地进攻癌细胞。钻研人员指出 ，好多人对基因疗法心存疑虑 ，不安病人的基因在接受医治后产生扭转 ，引发更多的不良反映。然而 ，上述钻研并不存在这种风险 ，由于番茄基因仅仅被注入癌细胞内 ，并不影响其他细胞。 新华网 2010-3-29 12:11:30
【点评】
细胞造就以及裸鼠尝试显示 西红柿TK1基因与抗艾滋药物逆转录酶抑造剂AZT组合的自杀基因疗法结合干细胞介导的基因注入 显著提高了癌细胞对药物的敏感度 ，内容性的抑造了肿瘤成长 ，能够说在针对癌细胞的攻击方面这简直是个很好的战术 ，只是一方面还仅仅在尝试动物身上看到成效 ，另一方面 ，它并未有显示出能够治愈癌症的潜力 ，并且将异种基因转入动物体内哪怕只是体内的癌细胞中会产生什么后果尚未可知 ，也就存在着未知的风险。最根基的 ，这种战术依然是治标不治本。
【原文摘录】
Neuro Oncol. 2010 Feb 13 PMID: 20154339
Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy.
Khan Z, Knecht W, Willer M, Rozpedowska E, Kristoffersen P, Clausen AR, Munch-Petersen B, Almqvist PM, Gojkovic Z, Piskur J, Ekstr?m TJ.
The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen for central nervous system (CNS) tumors, several obstacles have been encountered such as inefficient gene transfer to the tumor cells, limited prodrug penetration into the CNS, and inefficient enzymatic activity of the suicide gene. We report here the cloning and successful application of a novel thymidine kinase 1 (TK1) from the tomato plant, with favorable characteristics in vitro and in vivo. This enzyme (toTK1) is highly specific for the nucleoside analog prodrug zidovudine (azidothymidine, AZT), which is known to penetrate the blood-brain barrier. An important feature of toTK1 is that it efficiently phosphorylates its substrate AZT not only to AZT monophosphate, but also to AZT diphosphate, with excellent kinetics. The efficiency of the toTK1/AZT system was confirmed when toTK1-transduced human glioblastoma (GBM) cells displayed a 500-fold increased sensitivity to AZT compared with wild-type cells. In addition, when neural progenitor cells were used as delivery vectors for toTK1 in intracranial GBM xenografts in nude rats, substantial attenuation of tumor growth was achieved in animals exposed to AZT, and survival of the animals was significantly improved compared with controls. The novel toTK1/AZT suicide gene therapy system in combination with stem cell-mediated gene delivery promises new treatment of malignant gliomas.
5. 一种可使药物直接攻击癌细胞的全新步骤
【提要】
加拿大蒙特利尔大学和拉瓦尔大学的科学家发现了一种可使药物直接攻击癌细胞的全新步骤 ，其可为急性骨髓白血病患者等癌症病人带来福音。据科学家称 ，这种新步骤目前已靠近于临床试验。有关文章颁发在最新出版的《生物化学杂志》上。 钻研掌管人、蒙特利尔大学药学系教授丁戴尔•拉门塔尔暗示 ，他们发现人体中部门类型的细胞存在一个“门口” ，如源自骨髓的细胞就存在一个允许博来霉素等抗癌药物进入的“门” ，找到并打开这扇“门”就可让药物直接攻击引发白血病的癌细胞。该成就为癌症医治启发了一条新蹊径。
拉门塔尔教授介绍 ，他在十年前起头将该理论付诸实际 ，在与人体细胞极度靠近的发酵用酵母上进行了试验。目前所获发现正是基于酵母尝试的成就 ，新步骤可被利用于人体细胞 ，并能很快进入临床医治。
据介绍 ，新步骤对于癌症患者出格是急性骨髓白血病患者实属福音。急性骨髓白血病影响人的白细胞 ，这种癌症极度难医治 ，绝大部门患者对各类抗癌药物没有反映。拉门塔尔教授暗示 ，新步骤能够将抗癌药剂以束流的大局医治急性骨髓白血病。他说：“例如我们发现博来霉素等抗癌药剂对来自患者身上的淋巴瘤细胞拥有正面了局 ，但同时还要依附‘门口’的存在。”由于博来霉素不阐发为免疫抑造剂 ，他以为这对患者来说是一个极度利好的新闻。
拉门塔尔教授还提醒到 ，新找到的“门口”只存在于部门细胞类型 ，好比那些来自于骨髓的细胞 ，但对于乳腺癌等就不起作用 ，这样就很难使用博来霉素等来医治乳腺癌患者。因而 ，他以为目前应着手寻找可能刺激“门口”产生的方式 ，这样才可能使用博来霉素等药物医治更多类型的癌症
【点评】
寻找可能刺激“门口”产生的方式是没准的事件 ，要寻找只刺激癌细胞“门口”产生的方式 ，不影响正常细胞 ，更难。总之不能解决药物对癌细胞和正常细胞的类似作用 ，化疗的远景就无法看好。若是能像再生营养物质那样在有利于正常细胞的同时扑灭癌细胞 ，把看似矛盾的两个方面统一路来做到两全其美。这才是癌症医治的最好了局。
【原文摘录】
JBC doi: 10.1074/jbc.M109.046151
The Human Carnitine Transporter SLC22A16 Mediates High Affinity Uptake of the Anticancer Polyamine Analogue Bleomycin-A5*
Mustapha Aouida,1, Richard Poulin§ and Dindial Ramotar,2
Bleomycin is used in combination with other antineoplastic agents to effectively treat lymphomas, testicular carcinomas, and squamous cell carcinomas of the cervix, head, and neck. However, resistance to bleomycin remains a persistent limitation in exploiting the full therapeutic benefit of the drug with other types of cancers. Previously, we documented that the Saccharomyces cerevisiae L-carnitine transporter Agp2 is responsible for the high affinity uptake of polyamines and of the polyamine analogue bleomycin-A5. Herein, we document that the human L-carnitine transporter hCT2 encoded by the SLC22A16 gene is involved in bleomycin-A5 uptake, as well as polyamines. We show that NT2/D1 human testicular cancer cells, which highly express hCT2, are extremely sensitive to bleomycin-A5, whereas HCT116 human colon carcinoma cells devoid of detectable hCT2 expression or MCF-7 human breast cancer cells that only weakly express the permease showed striking resistance to the drug. NT2/D1 cells accumulated fluorescein-labeled bleomycin-A5 to substantially higher levels than HCT116 cells. Moreover, L-carnitine protected NT2/D1 cells from the lethal effects of bleomycin-A5 by preventing its influx, and siRNA targeted to hCT2 induced resistance to bleomycin-A5-dependent genotoxicity. Furthermore, hCT2 overexpression induced by transient transfection of a functional hCT2-GFP fusion protein sensitized HCT116 cells to bleomycin-A5. Collectively, our data strongly suggest that hCT2 can mediate bleomycin-A5 and polyamine uptake, and that the rate of bleomycin-A5 accumulation may account for the differential response to the drug in patients.
6. C60运载基因技术为糖尿病患者送福音
【提要】
日本东京大学的钻研人员初次开发出了利用超幼球形碳分子C60（富勒烯）导入基因的新技术。该技术有望为糖尿病患者带来福音。C60是60个碳原子结合在一路形成的直径不及1纳米的球状微幼粒子。东京大学副教授野入英世和教授中村荣一携带的钻研幼组让C60携带4个氨基 ，造作出了水溶性C60 ，使其与基因结合成为可能。
钻研人员将结合了绿色荧光蛋白基因的水溶性C60注射到尝试鼠体内。了局发现尝试鼠的肺、肝和脾都出现了该基因 ，证实了水溶性C60拥有壮大的基因运载能力 。在随后的尝试中 ，钻研人员让水溶性C60携带领导合成胰岛素的基因进入尝试鼠体内 ，了局尝试鼠体内的胰岛素水平增长到泛泛的1.5倍 ，血糖值也降低了20%以上。钻研人员介绍说 ，与基因结合的水溶性C60穿过细胞膜以来就会与基因分离 ，随尿液排出体表 ，不会在体内堆积。
目前 ，医治糖尿病的伎俩重要是通过给患者直接注射胰岛素来降低血糖值。日本钻研人员以为 ，这次开发的新技术达到实用化水平后 ，降低血糖值成效的持续功夫将比直接注射还要长 ，由此将大大减轻患者的职守。另表 ，这项新技术还有可能促成安全性更高的基因医治糖尿病步骤的出现。
【点评】
该技术若能发展成熟 ，可能会为RNAi技术更好的用于需基因医治的疾病提供很大援手。总之 ，这看上去是一项很好的基因运载技术。
【原文摘录】
PNAS doi: 10.1073/pnas.0909223107
In vivo gene delivery by cationic tetraamino fullerene
Rui Maeda-Mamiyaa,b, Eisei Noirib,1, Hiroyuki Isobec, Waka Nakanishic, Koji Okamotob, Kent Doib, Takeshi Sugayad, Tetsuro Izumie, Tatsuya Hommaa, and Eiichi Nakamuraa,1
Application of nanotechnology to medical biology has brought remarkable success. Water-soluble fullerenes are molecules with great potential for biological use because they can endow unique characteristics of amphipathic property and form a self-assembled structure by chemical modification. Effective gene delivery in vitro with tetra(piperazino)fullerene epoxide (TPFE) and its superiority to Lipofectin have been described in a previous report. For this study, we evaluated the efficacy of in vivo gene delivery by TPFE. Delivery of enhanced green fluorescent protein gene (EGFP) by TPFE on pregnant female ICR mice showed distinct organ selectivity compared with Lipofectin; moreover, higher gene expression by TPFE was found in liver and spleen, but not in the lung. No acute toxicity of TPFE was found for the liver and kidney, although Lipofectin significantly increased liver enzymes and blood urea nitrogen. In fetal tissues, neither TPFE nor Lipofectin induced EGFP gene expression. Delivery of insulin 2 gene to female C57/BL6 mice increased plasma insulin levels and reduced blood glucose concentrations, indicating the potential of TPFE-based gene delivery for clinical application. In conclusion, this study demonstrated effective gene delivery in vivo for the first time using a water-soluble fullerene.
7. 基因疗法复原患眼疾幼鼠视力
【提要】
据国表媒体报路 ，来自美国纽约州布法罗视注俄亥俄州克利夫兰市和俄克拉何马州的科学家使用基因疗法 ，改善拥有视网膜色素变性疾病的老鼠视力。这一钻研了局批注 ，科学家在使盲人复原视力的路路上获得了长足的进取。据悉 ，〖国尝试生物学学会结合会杂志》2010年4月刊上颁发的一篇钻研汇报中 ，科学家具体论述了利用合成的纳米颗粒 ，改善拥有视网膜色素变性疾病老鼠视力的过程。视网膜色素变性是视网膜光感触器细胞和色素上皮细胞变性 ，从而导致夜盲和进行性视野缺损的一组拥有临床亚型的基因遗传性致盲眼病。
钻研幼组成员 ，俄克拉何马州奥克拉荷马大学健全科学中心细胞生物学下烦西博士和她的同事一路 ，钻研了一组带有视网膜缓慢变性基因的老鼠。莱西和她的同事对这些老鼠进行了三种分歧类型的医治步骤：一种步骤是用蕴含Rds基因的纳米颗粒来医治 ，一种步骤是用正�；蚶匆街� ，还有一种步骤是通过生理盐水来医治。 执行三种分歧类型的医治步骤后 ，钻研人员将尝试老鼠和其它拥有视网膜色素变性或视网膜缓慢变性疾病老鼠进行比力 ，从而分析得出尝试老鼠视网膜的职能和结构。钻研人员发现 ，接受纳米颗�；蛄品ǖ睦鲜� ，其视觉职能得到改善 ，拥有显著愈合的迹象 ，并且这种成效到尝试实现都还维持无缺 ，而接受正�；蚝蜕硌嗡街蔚睦鲜� ，其视力不休降落。上述尝试了局批注 ，纳米颗粒是耐受性优良 ，并且是安全无副作用的医治步骤。
钻研人员称 ，他们但愿此钻研了局可援手治愈那些和视网膜色素变性、遗传性疾病和后天视网膜疾病等导致失明的疾病。 〖国尝试生物学学会结合会杂志》杂志主编 ，杰拉尔• 德韦斯曼说：“使盲人复原视力已经被称为事业。随着我们对进化、遗传学和纳米技术理解的加深 ，这种神奇的医治步骤将变得十吩煺遍。”
【点评】
盲人复明是圣经中的神迹 ，是医学上的难题 ，上述基因疗法还只是在老鼠尝试中显示了效力 ，不外也能给盲人患者带来一丝进展 ，是基因医治的进取之一 ，固然基因疗法在临床利用上还很不成熟 ，也不确定到底能否成熟起来 ，终于这是在过问人体自身的遗传信息 ，会造成多大的影响 ，什么样的影响 ，我们并不明显。
【原文摘录】
Published as doi: 10.1096/fj.09-139147. (The FASEB Journal. 2010;24:1178-1191.)
Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa
Xue Cai*, Shannon M. Conley*, Zack Nash*, Steven J. Fliesler , , , Mark J. Cooper|| and Muna I. Naash*,1
The purpose of the present study was to test the therapeutic efficiency and safety of compacted-DNA nanoparticle-mediated gene delivery into the subretinal space of a juvenile mouse model of retinitis pigmentosa. Nanoparticles containing the mouse opsin promoter and wild-type mouse Rds gene were injected subretinally into mice carrying a haploinsufficiency mutation in the retinal degeneration slow (rds+/–) gene at postnatal day (P)5 and 22. Control mice were either injected with saline, injected with uncompacted naked plasmid DNA carrying the Rds gene, or remained untreated. Rds mRNA levels peaked at postinjection day 2 to 7 (PI-2 to PI-7) for P5 injections, stabilized at levels 2-fold higher than in uninjected controls for both P5 and P22 injections, and remained elevated at the latest time point examined (PI-120). Rod function (measured by electroretinography) showed modest but statistically significant improvement compared with controls after both P5 and P22 injections. Cone function in nanoparticle-injected eyes reached wild-type levels for both ages of injections, indicating full prevention of cone degeneration. Ultrastructural examination at PI-120 revealed significant improvement in outer segment structures in P5 nanoparticle-injected eyes, while P22 injection had a modest structural improvement. There was no evidence of macrophage activation or induction of IL-6 or TNF- mRNA in P5 or P22 nanoparticle-dosed eyes at either PI-2 or PI-30. Thus, compacted-DNA nanoparticles can efficiently and safely drive gene expression in both mitotic and postmitotic photoreceptors and retard degeneration in this model. These findings, using a clinically relevant treatment paradigm, illustrate the potential for application of nanoparticle-based gene replacement therapy for treatment of human retinal degenerations.—Cai, X., Conley, S. M., Nash, Z., Fliesler, S. J., Cooper, M. J., Naash, M. I. Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa.
8. DAF-16基因同寿命亲昵有关
【提要】
从遗传学角度钻研衰老机造的一组英国科学家4月1日在《公共科学图书馆•综合》网站撰文指出 ，他们针对尝试室蠕虫进行的钻研批注 ，DAF-16基因同寿命、免疫力亲昵有关。由于好多动物和人体内都占有DAF-16基因 ，该发现有助于更好地相识影响人类衰老和免疫职能的原因。全球各地的人们在大踏步迈向衰老 ，给健全和社会保险系统提出了巨大挑战。丹麦科学家去年进行的一项钻研发现 ，富足国度诞生的婴儿中 ，有一半将能够庆祝其百岁生日�？蒲Ъ壹逼劝屯赡苷业搅钊怂ダ系脑� ，据此研发出药物援手人们尽可能长命 ，并在有生之年维持健全。英国伯明翰大学的罗宾•梅尔辅导了这项钻研。梅尔团队比力了4种关系亲昵的蠕虫的寿命、抗药性以及免疫力情况 ，他们发现 ，这4种蠕虫体内的DAF-16基因的活性存在巨大的差距。更沉要的是 ，DAF-16活性的差距同寿命、抵抗力和免疫力相辅相成：DAF-16的活性越高 ，蠕虫的寿命越长 ，抗习染的免疫力越好。梅尔暗示 ，这批注 ，免疫力和衰老亲昵有关。物种之间的DAF-16基因的活性的差距对衰老和健全拥有极度沉要的影响 ，这或许能够诠释人与人之间的寿命为何分歧。
梅尔称 ，DAF-16在体内大无数细胞中都很活跃 ，它们同人体内的FoxO家族调节基因极度类似 ，科学家以为FOXO家族在动物细胞的分化、成长、增殖、代谢、免疫及衰老调节方面拥有多样性职能。英国生物技术和生物科学钻研协会掌管人路格拉斯•凯尔暗示 ，这个发现将援手科学家理解决定人类衰老的有关机造。
【点评】
在分子机造上钻研衰老和免疫 ，进展可能找到令人衰老的原因 ，据此研发出药物援手人们尽可能长命 ，并在有生之年维持健全。在复杂的分子调控网络档次是做这项钻研 ，即便有但愿 ，也还有很漫长的路要走。而在细胞水平上的钻研 ，人体再生复原科学则已经找到了预防衰老的蹊径并在用于人体养生。
【原文摘录】
Phenotypic Covariance of Longevity, Immunity and Stress Resistance in the Caenorhabditis Nematodes
Francis R. G. Amrit, Claudia M. L. Boehnisch, Robin C. May*
Abstract
Background
Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin–like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four Caenorhabditis species.
Methodology/Principal Findings
We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis.
Conclusions
The gonochoristic species display a significantly longer lifespan (p<0.0001) and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants。