世界生命科學前沿動態(tài)周報（二十一）

（08.23 --08.29/ 2010）
美寶國際集團:陶國新 

　　本周動態(tài)包括以下內容： 體內葡萄糖含量過高影響免疫系統(tǒng) ; MIT 科學家發(fā)明人類干細胞培養(yǎng)新方法； 骨髓移植治療 大皰性表皮松解癥； 生物合成角膜有助視力恢復；科學家 確認血脂代謝相關基因座 。

•  體內葡萄糖含量過高影響免疫系統(tǒng)
【摘要】 來源：科技日報 發(fā)布時間： 2010-8-27 17:13:23

　　糖尿病患者除易患腎臟疾病等并發(fā)癥外，也很容易被慢性細菌和真菌感染而患上炎癥性疾病。對于這類并發(fā)癥的病理機制，醫(yī)學界一直不太清楚。英國華威大學最新研究表明，這是由于人體內葡萄糖水平過高影響了免疫系統(tǒng)，抑制其功能發(fā)揮造成的。華威大學 8 月 25 日發(fā)布的公報中稱，該校研究人員對人體血液和體液中的葡萄糖和另外兩種糖——甘露糖和巖藻糖的化學結構進行了分析。甘露糖和巖藻糖是人體免疫受體識別細菌和真菌的標記，免疫受體會與這兩種微糖綁定來對抗感染。研究人員發(fā)現，人體內葡萄糖水平一旦過高，其就會代替甘露糖和巖藻糖綁定免疫受體，從而妨礙免疫受體識別感染性細菌和真菌。這種越俎代庖的行為，會抑制人體對抗感染的正常進程。它會抑制人體免疫系統(tǒng) C 型凝集素的功能。這些凝集素中，包括甘露糖結合凝集素（ MBL ），其功能失效，則會使人更易患上炎癥性疾??；它也會影響免疫細胞表面受體 DC-SIGN 和 DC-SIGNR ，這兩種受體存在于白血球、血小板、血管內皮細胞等循環(huán)和血管系統(tǒng)的關鍵部位中，它們的功能受到抑制，則會導致糖尿病人出現心血管和腎臟并發(fā)癥。  

　　華威大學醫(yī)學院的丹尼爾· 米切爾 博士表示，葡萄糖水平與人體免疫系統(tǒng)之間的這種關系，使科學家對高葡萄糖對免疫系統(tǒng)和身體健康的影響有了新的認識。而日常生活中保持合理的飲食結構，控制血糖水平則更顯得重要。他們將基于新發(fā)現來完善糖尿病疾病模型，以尋找新的防治手段。

【點評】

　　該項研究發(fā)現了人體內 高水平葡萄糖會通過競爭性抑制來干擾免疫受體對寡糖的體識，進而妨礙免疫受體識別感染性細菌和真菌，抑制人體對抗感染的正常進程。對于人類，尤其是糖尿病人，重新認識高血糖的生理意義及其對糖尿病并發(fā)癥的作用有重要影響。同時也提醒人們日常飲食攝入過多的糖分很可能會降低你的身體免疫力。

【原文摘錄 】   Immunobiology doi:10.1016/j.imbio.2010.06.002 

High glucose disrupts oligosaccharide recognition function via competitive inhibition: A potential mechanism for immune dysregulation in diabetes mellitus.

Ilyas R , Wallis R , Soilleux EJ , et al.

Diabetic complications include infection and cardiovascular disease. Within the immune system, host-pathogen and regulatory host-host interactions operate through binding of oligosaccharides by C-type lectin. A number of C-type lectins recognise oligosaccharides rich in mannose and fucose - sugars with similar structures to glucose. This raises the possibility that high glucose conditions in diabetes affect protein-oligosaccharide interactions via competitive inhibition. Mannose-binding lectin, soluble DC-SIGN and DC-SIGNR, and surfactant protein D, were tested for carbohydrate binding in the presence of glucose concentrations typical of diabetes, via surface plasmon resonance and affinity chromatography. Complement activation assays were performed in high glucose. DC-SIGN and DC-SIGNR expression in adipose tissues was examined via immunohistochemistry. High glucose inhibited C-type lectin binding to high-mannose glycoprotein and binding of DC-SIGN to fucosylated ligand (blood group B) was abrogated in high glucose. Complement activation via the lectin pathway was inhibited in high glucose and also in high trehalose - a nonreducing sugar with glucoside stereochemistry. DC-SIGN staining was seen on cells with DC morphology within omental and subcutaneous adipose tissues. We conclude that high glucose disrupts C-type lectin function, potentially illuminating new perspectives on susceptibility to infectious and inflammatory disease in diabetes. Mechanisms involve competitive inhibition of carbohydrate binding within sets of defined proteins, in contrast to broadly indiscriminate, irreversible glycation of proteins.

•  MIT 科學家發(fā)明人類干細胞培養(yǎng)新方法

【摘要】

　　多功能干細胞能夠分化成其他任何一種體細胞，在治療各種疾病方面具有很大潛力。但是，如何培養(yǎng)足夠量的多功能干細胞對研究者來說是個問題；此外，目前用于培養(yǎng)人類干細胞的材料會導致免疫反應。為了克服這些問題，以美國麻省理工學院（ MIT ）科學家為首的研究小組發(fā)明了一種合成性基質（ synthetic substrate ）。這種基質沒有外來動物材料，能夠使干細胞至少三個月保持活性并自我繁殖。而且，該合成性基質首次使得單細胞能夠形成細胞集落。相關研究發(fā)表在 8 月 22 日的《自然—材料學》（ Nature Materials ）上。

　　以往研究表明，基質表面的化學和物理特性，比如粗糙度、硬度、對水的親和力等對干細胞生長有影響。 MIT 研究人員創(chuàng)造了 500 種特性不同的聚合物并在上面培養(yǎng)干細胞，分析每個聚合物上面細胞的生長狀況。他們發(fā)現， 基質表面疏水性 對細胞生長有個最佳范圍，而表面糙度和硬度則沒有太多影響。此外，他們調整最佳聚合物的組成為：高比例的丙烯酸酯，外面包裹玻連蛋白。應用這種新的培養(yǎng)基質， MIT 科學家成功實現了人類胚胎干細胞持續(xù)三個月的生長和分裂，并獲得了大量的細胞。他們將進一步研究，爭取將這種培養(yǎng)基質應用到其它類細胞。（ 來源： 科學網 www.sciencenet.cn 發(fā)布時間： 2010-8-24 10:43:34 ）

【點評】

　　新的培養(yǎng)基質可以使干細胞長時間保持活性和自我繁殖，對于解決干細胞研究中獲取大量干細胞的問題有很大幫助。雖然不能因此使干細胞治療有實質性進展，但至少有助于干細胞的實驗研究。

【原文摘錄】 Nature Materials 9, 768–778 doi:10.1038/nmat2812

Combinatorial development of biomaterials for clonal growth of human pluripotent stem cells

Ying Mei , Krishanu Saha , Said R. Bogatyrev ， et al.

Both human embryonic stem cells and induced pluripotent stem cells can self-renew indefinitely in culture; however, present methods to clonally grow them are inefficient and poorly defined for genetic manipulation and therapeutic purposes. Here we develop the first chemically defined, xeno-free, feeder-free synthetic substrates to support robust self-renewal of fully dissociated human embryonic stem and induced pluripotent stem cells. Material properties including wettability, surface topography, surface chemistry and indentation elastic modulus of all polymeric substrates were quantified using high-throughput methods to develop structure–function relationships between material properties and biological performance. These analyses show that optimal human embryonic stem cell substrates are generated from monomers with high acrylate content, have a moderate wettability and employ integrin α v β 3 and α v β 5 engagement with adsorbed vitronectin to promote colony formation. The structure–function methodology employed herein provides a general framework for the combinatorial development of synthetic substrates for stem cell culture.

•  骨髓移植治療 大皰性表皮松解癥
【摘要】 NEJM 發(fā)布時間： 2010-8-25 15:33:04

　　大皰性表皮松解癥是由于皮膚結構蛋白的先天性缺陷，使皮膚容易發(fā)生松解出現大皰。如單純性大皰性表皮松解癥是由于表皮基底細胞的結構蛋白 -- 角蛋白 5 或角蛋白 14 的缺陷所致；交界性大皰性表皮松解癥是由于 BPAG2 或板素 (Laminin)5 的缺陷所致；營養(yǎng)不良型大皰性表皮松解癥則是由于基底膜帶中 Ⅶ 型膠原蛋白的缺陷所致?，F已弄清缺陷的發(fā)生是因為這些編碼蛋白的基因出現了突變，導致蛋白質的結構異常，使皮膚松解。盡管遺傳學基礎已被闡明，但仍無有效的治療。大皰性表皮松解的治療主要針對其繼發(fā)感染，原則為精心護理，保護局部，避免外傷、摩擦受熱防止繼發(fā)感染。利用干細胞產生新的組織和器官，修復破損的組織、器官，被稱為再生醫(yī)學。 美國《新英格蘭醫(yī)學雜志》（ NEJM ） 8 月 11 日刊登明尼蘇達大學研究者約翰· 瓦格納和雅各布·托拉爾的研究報告，首次顯示骨髓干細胞可用于治療營養(yǎng)不良型大皰性表皮松解癥，為根除這一頑疾帶來了希望。

【點評】

　　用于 6 名大皰性表皮松解癥患者的同種異體骨髓移植的實驗性臨床治療為從根本上治愈這一頑癥提供了一種可能，盡管這一方法的長期風險和效果還有待進一步評估。另一方面，該研究也提示該治療中骨髓干細胞可能是分化成正常皮膚組織的來源。

【原文摘錄 】 N Engl J Med 2010; 363:629-639 August 12, 2010

Bone Marrow Transplantation for Recessive Dystrophic Epidermolysis Bullosa

John E. Wagner, M.D., Akemi Ishida-Yamamoto, M.D., Ph.D., John A. McGrath, M.D., et al.

Background

Recessive dystrophic epidermolysis bullosa is an incurable, often fatal mucocutaneous blistering disease caused by mutations in COL 7A 1, the gene encoding type VII collagen (C7). On the basis of preclinical data showing biochemical correction and prolonged survival in col7 −/− mice, we hypothesized that allogeneic marrow contains stem cells capable of ameliorating the manifestations of recessive dystrophic epidermolysis bullosa in humans.

Methods

Between October 2007 and August 2009, we treated seven children who had recessive dystrophic epidermolysis bullosa with immunomyeloablative chemotherapy and allogeneic stem-cell transplantation. We assessed C7 expression by means of immunofluorescence staining and used transmission electron microscopy to visualize anchoring fibrils. We measured chimerism by means of competitive polymerase-chain-reaction assay, and documented blister formation and wound healing with the use of digital photography.

Results

One patient died of cardiomyopathy before transplantation. Of the remaining six patients, one had severe regimen-related cutaneous toxicity, with all having improved wound healing and a reduction in blister formation between 30 and 130 days after transplantation. We observed increased C7 deposition at the dermal–epidermal junction in five of the six recipients, albeit without normalization of anchoring fibrils. Five recipients were alive 130 to 799 days after transplantation; one died at 183 days as a consequence of graft rejection and infection. The six recipients had substantial proportions of donor cells in the skin, and none had detectable anti-C7 antibodies.

Conclusions

Increased C7 deposition and a sustained presence of donor cells were found in the skin of children with recessive dystrophic epidermolysis bullosa after allogeneic bone marrow transplantation. Further studies are needed to assess the long-term risks and benefits of such therapy in patients with this disorder.

•  生物合成角膜有助視力恢復
【摘要】 來源：《科學—轉化醫(yī)學》 發(fā)布時間： 2010-8-27 16:22:22

　　加拿大和瑞典科研人員研制出一種生物合成角膜，幫助眼疾患者修復受損眼組織，恢復視力。由加拿大渥太華醫(yī)院研究所研究員梅·格里菲思和瑞典林雪平大學眼科學教授佩爾·法格霍爾姆領導的一個研究小組將 10 名患者角膜中的受損組織移除后，植入人造角膜。術后，研究人員經過兩年多的跟蹤觀察，發(fā)現其中 9 名患者的人造角膜與眼球其他細胞融合。研究人員說，接受移植后的眼球開始分泌淚液。 6 名患者的視力逐漸恢復。“這項研究第一次表明，人造角膜可以與人的眼球融合并激發(fā)組織再生 , ”格里菲斯說：“隨著研究的深入，這種方式能幫助數以百萬計等待角膜移植的人恢復視力?！苯悄な茄矍虮砻娓采w的一層透明、膠片狀組織，主要成分是蛋白膠原質，能夠折射光線，將景物成像于視網膜上。盡管角膜容易受到外傷或感染而受損，但眼下的醫(yī)學技術能夠通過角膜移植手術令患者恢復視力。研究人員說，由于眼角膜捐獻數量有限，全球每年有許多人因角膜受傷致殘。他們這項研究成果有助于這些眼疾患者重見光明。

【點評】

　　兩年多跟蹤觀察 10 名移植了人造角膜的患者， 9 名患者的人造角膜與眼球其他細胞融合， 6 名患者的視力逐漸恢復。長期效果有待觀察，但這項研究第一次表明，人造角膜可以與人的眼球融合并激發(fā)組織再生，有可能幫助因角膜受傷致殘患者重見光明。在醫(yī)用材料而言是一大突破。

【原文摘錄 】 Sci Transl Med Vol. 2, Issue 46, p. 46ra61 DOI: 10.1126/scitranslmed.3001022

A Biosynthetic Alternative to Human Donor Tissue for Inducing Corneal Regeneration: 24-Month Follow-Up of a Phase 1 Clinical Study

Per Fagerholm , Neil S. Lagali , Kimberley Merrett , et al.

Corneas from human donors are used to replace damaged tissue and treat corneal blindness, but there is a severe worldwide shortage of donor corneas. We conducted a phase 1 clinical study in which biosynthetic mimics of corneal extracellular matrix were implanted to replace the pathologic anterior cornea of 10 patients who had significant vision loss, with the aim of facilitating endogenous tissue regeneration without the use of human donor tissue. The biosynthetic implants remained stably integrated and avascular for 24 months after surgery, without the need for long-term use of the steroid immunosuppression that is required for traditional allotransplantation. Corneal reepithelialization occurred in all patients, although a delay in epithelial closure as a result of the overlying retaining sutures led to early, localized implant thinning and fibrosis in some patients. The tear film was restored, and stromal cells were recruited into the implant in all patients. Nerve regeneration was also observed and touch sensitivity was restored, both to an equal or to a greater degree than is seen with human donor tissue. Vision at 24 months improved from preoperative values in six patients. With further optimization, biosynthetic corneal implants could offer a safe and effective alternative to the implantation of human tissue to help address the current donor cornea shortage.

•  科學家確認血脂代謝相關基因座
【摘要】 《自然》 發(fā)布時間： 2010-8-25 17:47:46

　　血液中總膽固醇、低密度脂蛋白膽固醇、高密度脂蛋白膽固醇和甘油三酯等脂類含量是導致冠狀動脈疾病（ CAD ）的最重要危險因素，同時也是防治該種疾病的重要標靶。一國際研究小組在《自然》（ Nature ）雜志上刊登報告稱，他們研究確認了 95 個與人類血脂代謝相關的基因座，可作為冠狀動脈疾病的生物學標記。研究人員稱，新研究不僅擴展了科學家對人體脂類代謝的理解視野，同時也為開發(fā)新型防治冠狀動脈疾病的靶向型藥物奠定了基礎。 該國際研究小組由英美等多國近百位科學家組成，他們對超過 10 萬名具有歐洲血統(tǒng)的志愿者的基因進行了分析，最終確認了 95 個與脂類代謝相關的基因座，其中有 59 個基因座是首次被認定。這 95 個基因座不僅會導致人體內脂類特性的一般性改變，而且還會導致極端的脂類表型。研究結果表明，一些新發(fā)現的基因座與冠狀動脈疾病有關。研究人員還就 GALNT2 、 PPP1R3B 和 TTC39B 這三種新基因在小鼠模型上進行了驗證。  

　　研究人員表示，此項研究是目前就人體脂類代謝機制生物學基礎問題所進行的最全面的分析研究，其目的是要找到血液中脂類聚集的生物學標記，以作為冠狀動脈疾病發(fā)展的指標。研究結果則表明，通過抑制這些與脂類代謝有關的關鍵基因，可以起到預防心臟疾病的作用，這為開發(fā)新的靶向型藥物提供了基礎。英國倫敦國王大學的馬西莫·曼 吉諾 博士指出，這項研究對于科學家掌握冠狀動脈疾病的風險因素很有幫助。雖然研究對象是具有歐洲血統(tǒng)的志愿者，但研究人員發(fā)現，這些基因座并非歐洲人獨有，其對三個非歐洲人群體（東亞人、南亞人以及非洲裔美國人）的脂類特性也會產生重要影響。作為此方面迄今為止最大規(guī)模的研究，超大的樣本量使得該結果同樣具有國際意義。（來源：科技日報 劉海英 / 劉霞）

【點評】

　　作為就人體脂類代謝機制生物學基礎問題所進行超大樣本量的最全面的分析研究，對于科學家掌握冠狀動脈疾病的風險因素很有幫助。但是否因此就能發(fā)展出更好的治療冠狀動脈疾病的療法或藥物還看不出來。

【原文摘錄 】 Nature doi:10.1038/nature09270
Biological, clinical and population relevance of 95 loci for blood lipids

Tanya M. Teslovich , Kiran Musunuru , Albert V. Smith , et al.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci ( P < 5 × 10 −8 ), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP 7A 1 , NPC 1L 1 and SCARB1 ) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes— GALNT2 , PPP1R3B and TTC39B —with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.