世界生命科學前沿動態(tài)周報（三十四）

（11.29 -- 12.05 / 2010）
美寶國際集團:陶國新 

　　本周動態(tài)包括以下內(nèi)容：老鼠實驗表明修復端?？梢阅孓D(zhuǎn)衰老；發(fā)現(xiàn)新的抗癌免疫細胞；Lkb1促進造血干細胞生存；成熟血細胞與其親代干細胞的信息反饋；分子“開關(guān)”影響衰老和代謝疾病；共生菌影響果蠅的交配傾向。

1. 老鼠實驗表明修復端?？梢阅孓D(zhuǎn)衰老
【摘要】
　　據(jù)香港《文匯報》11月30日報道，哈佛科學家最近破天荒地令年老的老鼠器官獲得新生，成功逆轉(zhuǎn)衰老過程，這項突破成果或有望防治腦退化癥(老人癡呆癥)、糖尿病和心臟病等疾病，甚至有望打開永恒青春的奧秘，進一步邁向研制“長生不老藥”?？茖W雜志《自然》網(wǎng)站28日刊登美國哈佛醫(yī)學院的科研報告，研究員飼養(yǎng)了一些經(jīng)基因改造的老鼠，令它們因缺乏“端粒酶”(telomerase)而未老先衰，出現(xiàn)嗅覺衰退、腦部縮小、不育、腸部和脾臟受損等疾病，使它們皮膚、大腦、內(nèi)臟和其它器官老化。
所謂“端?！保侵溉旧w末端的DNA重復序列，作用是保持染色體的完整性?！岸肆！钡拈L度反映著細胞復制史及復制潛能，被稱作細胞壽命的“有絲分裂鐘”。報道稱，科研人員將這些老鼠分為兩組，把一種名為“4-羥基他莫昔芬”的定時釋放藥物，植入其中一組老鼠的皮下，重啟它們體內(nèi)休眠的“端粒酶”基因。結(jié)果在短短1個月內(nèi)，注射藥物的老鼠體內(nèi)長出許多新的細胞，主要器官運作功能改善，身體差不多完全“返老還童”，雄性老鼠更恢復生育功能。注射藥物的實驗鼠最終活到正常鼠的壽命，但并不比普通鼠壽命長。
進行研究的德皮尼奧博士表示，實驗鼠對人類而言，就像一個40歲的人，身體未老先衰像80多歲的老人，而這項實驗逆轉(zhuǎn)衰老過程，把他變回50歲一般。德皮尼奧說：“這些是嚴重衰老的動物，但經(jīng)過一個月治療后，它們已有具體康復跡象，包括腦部長出新的細胞?！彼赋?，這是首次有老鼠實驗成功把衰老過程逆轉(zhuǎn)，意味著一些老化的器官也有“重生”的可能。
不過，要把這一科技應用于人體身上將會較為困難，老鼠一生中都能制造端粒酶，但是人類到成年后便會自動“關(guān)掉”這種基因，從而阻止細胞增長失控，以免轉(zhuǎn)化成癌癥。因此，提升人體的“端粒酶”水平雖然或有助減緩衰老速度，但同時增加患癌的風險。德皮尼奧認為，“TERT”療法如果是分階段進行，和只用于身體沒有癌細胞及較為年青的人身上，療法或?qū)θ梭w安全。牛津大學生物化學家考克斯認為，這項研究“非常重要”，證明原則上短期恢復成人體內(nèi)的“端粒”，能令年老的組織重生和恢復生理功能。（來源：中國新聞網(wǎng) 發(fā)布時間：2010-11-30 11:05:34）

【點評】
　　該基因改造老鼠試驗第一次在動物身上實現(xiàn)了通過修復端粒而“返老還童”，雖然在正常衰老的老鼠身上還未有研究以及應用在人體上還遙遙無期，但是它證明了復原端?？梢阅孓D(zhuǎn)衰老。這在動物實驗方面為人體再生復原科學再添有利證據(jù)，證明衰老組織是可以復原到年輕態(tài)的。

【原文摘錄】Nature advance online publication doi:10.1038/nature09603
Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice
Mariela Jaskelioff, Florian L. Muller, Ji-Hye Paik, et al.
An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo1. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2+ neural progenitors, Dcx+ newborn neurons, and Olig2+ oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.

2. 發(fā)現(xiàn)新的抗癌免疫細胞

【摘要】
　　丹麥科研人員不久前發(fā)現(xiàn)一種新的免疫細胞能協(xié)助抵抗癌癥。他們正據(jù)此研制一種新型癌癥疫苗，目前正在進行臨床試驗。人體免疫抑制細胞和癌細胞可以產(chǎn)生一種特殊的雙加氧酶，來抑制免疫細胞的攻擊性，使其缺乏足夠攻擊力抵抗癌細胞侵襲，甚至還會被癌細胞吞噬。雙加氧酶的存在使現(xiàn)有癌癥疫苗的有效性大打折扣。丹麥海萊烏醫(yī)院癌癥免疫治療中心的研究者在最新一期美國學術(shù)刊物《血液》上報告說，他們發(fā)現(xiàn)人體免疫系統(tǒng)中存在一種此前未知的細胞，這種細胞可以殺死那些產(chǎn)生雙加氧酶的細胞。新發(fā)現(xiàn)的細胞在消滅免疫抑制細胞的同時，還能直接攻擊癌細胞。
領(lǐng)導這項研究的馬斯·哈爾·安德森說，研究小組正在研制一種新型癌癥疫苗，通過增加上述抗癌細胞的數(shù)量，提高機體免疫系統(tǒng)的攻擊力，從而抵抗癌癥。海萊烏醫(yī)院正用新疫苗對一些肺癌患者開展臨床試驗，目前的治療效果明顯好于常規(guī)療法。研究小組認為，從原理上說，這種可有效抑制雙加氧酶產(chǎn)生的癌癥疫苗有望與其他療法協(xié)同治療多種癌癥。（來源：新華網(wǎng) 2010-12-2 10:33:22）

【點評】
新的免疫細胞既能消滅免疫抑制細胞，還能直接攻擊癌細胞，對于對抗癌細胞是好消息。但是另一方面，新的免疫細胞的數(shù)量和活力需要小心控制，是否會導致自體免疫問題也需要進一步澄清。

【原文摘錄】Blood, Nov 2010; doi:10.1182/blood-2010-06-288498
Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators
Rikke Bæk Sørensen, Sine Reker Hadrup, Inge Marie Svane, et al.
Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in normal and pathological settings. Here, we describe that spontaneous cytotoxic T-cell reactivity against IDO exists not only in cancer patients but also in healthy individuals. We show that the presence of such IDO-specific CD8+ T cells boosted T-cell immunity against viral or tumor-associated antigens by eliminating IDO+ suppressive cells. This had profound effects on the balance between IL-17-producing CD4+ T cells and regulatory T cells. Furthermore, this caused an increase in the production of the pro-inflammatory cytokines IL-6 and TNF- while decreasing the IL-10 production. Finally, the addition of IDO-inducing agents (i.e. the TLR9 ligand CpG, soluble CTLA4 or IFN-) induced IDO-specific T cells among PBMC from cancer patients as well as healthy donors. In the clinical setting, IDO may serve as an important and widely applicable target for immunotherapeutic strategies where IDO play a significant regulatory role. The present describe for the first time effector T cells with a general regulatory function that may play a vital role for the mounting or maintaining of an effective adaptive immune response. We suggest terming such effector T cells "supporter T cells".

3. Lkb1促進造血干細胞生存

【摘要】
　　造血干細胞對高能和氧化壓力非常敏感，對它們的靜止與增殖之間的平衡進行調(diào)控是響應代謝壓力、同時保持其長期再生能力所需要的。新的研究表明，Lkb1腫瘤抑制因子和代謝傳感器在維持造血細胞的能量平衡中起關(guān)鍵作用，被發(fā)現(xiàn)是細胞周期調(diào)控及能量平衡所必需的，造血干細胞細胞周期調(diào)節(jié)和生存對Lkb1的依賴性要強于其他造血細胞。

【點評】
　　對造血干細胞的生命屬性和代謝機制又多了些了解。

【原文摘錄】Nature doi:10.1038/nature09571
Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells
Daisuke Nakada, Thomas L. Saunders & Sean J. Morrison
Little is known about metabolic regulation in stem cells and how this modulates tissue regeneration or tumour suppression. We studied the Lkb1 tumour suppressor and its substrate AMP-activated protein kinase (AMPK), kinases that coordinate metabolism with cell growth. Deletion of the Lkb1 (also called Stk11) gene in mice caused increased haematopoietic stem cell (HSC) division, rapid HSC depletion and pancytopenia. HSCs depended more acutely on Lkb1 for cell-cycle regulation and survival than many other haematopoietic cells. HSC depletion did not depend on mTOR activation or oxidative stress. Lkb1-deficient HSCs, but not myeloid progenitors, had reduced mitochondrial membrane potential and ATP levels. HSCs deficient for two catalytic α-subunits of AMPK (AMPK-deficient HSCs) showed similar changes in mitochondrial function but remained able to reconstitute irradiated mice. Lkb1-deficient HSCs, but not AMPK-deficient HSCs, exhibited defects in centrosomes and mitotic spindles in culture, and became aneuploid. Lkb1 is therefore required for HSC maintenance through AMPK-dependent and AMPK-independent mechanisms, revealing differences in metabolic and cell-cycle regulation between HSCs and some other haematopoietic progenitors.

4. 成熟血細胞與其親代干細胞的信息反饋

【摘要】
　　澳大利亞墨爾本W(wǎng)alter and Eliza Hall Institute的一項最新研究表明成熟血細胞能夠與親代干細胞“溝通”，并影響其行為。機體內(nèi)血細胞反饋環(huán)的發(fā)現(xiàn)為研究干細胞機能紊亂引起的疾病及開發(fā)新的治療方法開辟了新道路。研究結(jié)果發(fā)表在11月29日的PNAS上，揭示了從前未知的血細胞間的相互關(guān)系。
來自分子醫(yī)學系的Carolyn de Graaf博士和Doug Hilton教授以及來自癌癥和血液病學系的Warren Alexander領(lǐng)導了該項研究。“我們知道血液干細胞可生成所有類型的成熟血細胞?？茖W家們一直猜想是外部的因素調(diào)控了血細胞生成，并且兩個群體相互孤立存在，”Hilton教授說：“然而新研究表明成熟細胞事實上可反作用于干細胞，改變其基因表達以及影響它們的行為?！毖芯咳藛T發(fā)現(xiàn)血細胞異?？梢鸱答伃h(huán)失調(diào)，進而對血液干細胞產(chǎn)生影響。研究人員在動物模型中研究了一種抑制血小板生成的轉(zhuǎn)錄因子Myb，在檢測Myb缺失對細胞的影響時發(fā)現(xiàn)了這一現(xiàn)象。de Graaf博士說Myb基因缺失可導致動物血液中產(chǎn)生高水平的血小板，從而引起維持干細胞的信號途徑發(fā)生改變?！爱斝盘柾緩桨l(fā)生改變時，這些干細胞不再維持在一種‘靜止狀態(tài)’，而是在不斷地循環(huán)，生成成熟干細胞，”de Graaf博士說：“最終干細胞會耗盡，由于缺乏足夠的干細胞生成新的紅細胞和白細胞，從而導致機體血液疾病發(fā)生。”此外，研究人員還利用新一代的基因組技術(shù)鑒定了缺陷信號所致的血液干細胞中的基因標記。這些基因標記有可能在將來用于診斷和輔助疾病治療?！叭绻覀兡軌蛄私膺@些基因在干細胞維持和血細胞生成中的重要作用，我們就能夠找到一些新途徑提高移植技術(shù)和血液疾病的治療，”de Graaf博士說。Hilton教授認為新發(fā)現(xiàn)將使那些干細胞衰竭的患者受益?！拔覀兯龅氖虑榫褪谴_定這些干細胞的衰竭是否是由于成熟血細胞和干細胞之間的錯誤溝通所致，這些發(fā)現(xiàn)將有可能促使我們找到新的途徑治療這些疾病，”Hilton教授說。（Science Daily 2010-12-1 10:23:13 ）

【點評】
　　干細胞的活動規(guī)律受到機體的系統(tǒng)調(diào)控，成熟細胞會反饋信息到調(diào)控體系來調(diào)節(jié)干細胞的活動。說明一個體系里的上下游部分不是相互獨立的，一個整體里的各個體是相互關(guān)聯(lián)的，一個個體的異常影響的不僅僅是自身。   
【原文摘錄】PNAS  doi: 10.1073/pnas.1016166108
Regulation of hematopoietic stem cells by their mature progeny
Carolyn A. de Graafa,b, Maria Kauppic, et al.
Thrombopoietin (TPO), acting through its receptor Mpl, has two major physiological roles: ensuring production of sufficient platelets via stimulation of megakaryocyte production and maintaining hematopoietic stem cell (HSC) quiescence. Mpl also controls circulating TPO concentration via receptor-mediated internalization and degradation. Here, we demonstrate that the megakaryocytosis and increased platelet mass in mice with mutations in the Myb or p300 genes causes reduced circulating TPO concentration and TPO starvation of the stem-cell compartment, which is exacerbated because these cells additionally exhibit impaired responsiveness to TPO. HSCs from MybPlt4/Plt4 mice show altered expression of TPO-responsive genes and, like HSCs from Tpo and Mpl mutant mice, exhibit increased cycling and a decline in the number of HSCs with age. These studies suggest that disorders of platelet number can have profound effects on the HSC compartment via effects on the feedback regulation of circulating TPO concentration.

5. 分子“開關(guān)”影響衰老和代謝疾病

【摘要】
　　來自Harvard School of Public Health的科學家發(fā)現(xiàn)一種分子“開關(guān)”能夠關(guān)閉某些細胞進程來抵抗衰老和代謝疾病。盡管還需要更多的研究，這一發(fā)現(xiàn)很可能有助于開發(fā)新的途徑來終止或減慢諸如2型糖尿病和心臟病等代謝疾病的進展。用基因改造的老鼠模型，研究衰老過程中轉(zhuǎn)錄輔抑制物SMRT (silencing mediator of retinoid and thyroid hormone receptors)蛋白的作用，發(fā)現(xiàn)衰老細胞積累了更多的SMRT蛋白。在大多數(shù)代謝組織中SMRT的表達和結(jié)合到PPAR受體隨年齡增加。SMRT通過RID1和RID2兩個結(jié)構(gòu)域調(diào)節(jié)核受體信號途徑。通過基因工程選擇性失活RID1，使SMRT結(jié)合轉(zhuǎn)移到RID2相關(guān)核受體，增強了細胞對氧化損傷的敏感性，引起早衰和相關(guān)代謝疾病伴有線粒體功能降低和抗氧化基因表達。

【點評】
　　該研究豐富了對于衰老的理解和抗老化途徑的探索。

【原文摘錄】Cell Metabolism, 2010; DOI: 10.1016/j.cmet.2010.11.007
Nuclear Receptor Corepressor SMRT Regulates Mitochondrial Oxidative Metabolism and Mediates Aging-Related Metabolic Deterioration.
Shannon M. Reilly, Prerna Bhargava, Sihao Liu, et al.
The transcriptional corepressor SMRT utilizes two major receptor-interacting domains (RID1 and RID2) to mediate nuclear receptor (NR) signaling through epigenetic modification. The physiological significance of such interaction remains unclear. We find SMRT expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues. Genetic manipulations to selectively disable RID1 (SMRTmRID1) demonstrate that shifting SMRT repression to RID2-associated NRs, notably PPARs, causes premature aging and related metabolic diseases accompanied by reduced mitochondrial function and antioxidant gene expression. SMRTmRID1 cells exhibit increased susceptibility to oxidative damage, which could be rescued by PPAR activation or antioxidant treatment. In concert, several human Smrt gene polymorphisms are found to nominally associate with type 2 diabetes and adiponectin levels. These data uncover a role for SMRT in mitochondrial oxidative metabolism and the aging process, which may serve as a drug target to improve health span.

6. 共生菌影響果蠅的交配傾向

【摘要】
　　通常認為交配傾向是在物種形成早期就確立的事情。該研究通過果蠅實驗發(fā)現(xiàn)體內(nèi)共生菌也會影響果蠅交配傾向。通過用不同食物喂養(yǎng)由同一群果蠅分成的兩組，而后混合兩組果蠅，發(fā)現(xiàn)果蠅傾向于和同組的果蠅交配，該傾向從第一代可持續(xù)至少37代。而喂食中加入抗生素能消除這種傾向性，表明是果蠅菌群的緣故。進一步研究表明這些共生菌會改變果蠅表皮的性信息素水平從而影響其交配傾向。

【點評】
越來越多的研究表明共生菌群對動物有著重要影響。

【原文摘錄】PNAS  DOI: 10.1073/pnas.1009906107
Commensal bacteria play a role in mating preference of Drosophila melanogaster
G. Sharon, D. Segal, J. M. Ringo, et al.
Development of mating preference is considered to be an early event in speciation. In this study, mating preference was achieved by dividing a population of Drosophila melanogaster and rearing one part on a molasses medium and the other on a starch medium. When the isolated populations were mixed, “molasses flies” preferred to mate with other molasses flies and “starch flies” preferred to mate with other starch flies. The mating preference appeared after only one generation and was maintained for at least 37 generations. Antibiotic treatment abolished mating preference, suggesting that the fly microbiota was responsible for the phenomenon. This was confirmed by infection experiments with microbiota obtained from the fly media (before antibiotic treatment) as well as with a mixed culture of Lactobacillus species and a pure culture of Lactobacillus plantarum isolated from starch flies. Analytical data suggest that symbiotic bacteria can influence mating preference by changing the levels of cuticular hydrocarbon sex pheromones. The results are discussed within the framework of the hologenome theory of evolution.