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[ARVO2013]视觉信号通路研究中的新动向
——美国杜克大学眼科中心Vadim Y. Arshavsky教授专访

玻璃体视网膜  作者:  V.Y.Arshavsky  2013/7/2 15:44:00
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内容概要:《国际眼科时讯》:Arshavsky医生,您致力于研究脊椎动物的感光细胞,这项先进研究将会为哪些疾病的治疗带来福音呢?

  <International Ophthalmology Times>:Dr. Arshavsky, your interest in many multifunctional aspects of the vertebrate photoreceptors is well known. What diseases’ treatment will benefit from your advanced research?

  《国际眼科时讯》:Arshavsky医生,您致力于研究脊椎动物的感光细胞,这项先进研究将会为哪些疾病的治疗带来福音呢?

  Dr. Arshavsky:The most interesting thing about photoreceptor biology today is that we can finally integrate the basic information about how this cell works with some ideas how to treat dysfunctions of the cells. In the first layer, you can think that this would be very beneficial for treating retinitis pigmentosa and similar degenerative diseases, typically inherited degenerative diseases of the retina. However, you can think a little bit beyond and you can start thinking about Dry AMD because Dry AMD is a very interesting disease from a pathobiological perspective which clearly has some components related to the pathology of retinal pigment epithelium and photoreceptors.

  I can illustrate it with a very interesting example. For instance the translocation surgery, when a surgeon can move the retina such as a degenerating part of the retina is now facing apparently normal part of the pigment epithelium. It’s very often failing because the part of the pigment epithelia facing this diseased part of the retina becomes diseased very rapidly as well. I am a deep believer that understanding photoreceptor biology and better understanding of photoreceptor pathobiology is very critical for reconciling these very important observations.

  Arshavsky医生:目前感光细胞生物学中,最受关注的莫过于我们成功地将细胞运作的基本信息及细胞功能异常的治疗这两方面有机结合。首先,这有助于治疗视网膜色素变性及类似的退行性病变,尤其是遗传性视网膜退行性变。但是更进一步,你会开始思考干性AMD,这是一种非常有趣的疾病,从病理生理学角度来看,该病与视网膜色素上皮和感光细胞有一定关联。

  举例说明,在(黄斑部视网膜)转位手术时,术者通过移动视网膜,将退化的视网膜移位至正常的视网膜色素上皮区域。移位到视网膜病变区域的这部分视网膜色素上皮往往也会迅速病变,因此手术失败率高。我坚定地认为,全面了解感光细胞的生物学和病理学,对于上述观察研究是非常重要的。

  <International Ophthalmology Times>:Can you envision then the next step, how will the treatment look now that you know about the photoreceptor cells?

  《国际眼科时讯》:以您对于感光细胞的了解和研究,能否展望下一步的研究方向,并谈谈对治疗前景的看法。

  Dr. Arshavsky:We are entering the age where there are multiple opportunities on the horizon. I think that the next very major step will be pharmaceuticals because today we know so much more about small molecules that deliver in the properties. But also in particular from scientific perspective, it’s very nice to look at the next horizons and think very carefully today about future stem cell therapies and maybe very interesting and novel applications, optogenetics to treating the cells, maybe endowing some other cells downstream in the pathway with their ability to see light and transfer information about light to the brain through the optogenetic techniques which are becoming more and more sophisticated now.

  Arshavsky医生:我们身处一个机会层出不穷的时代。接下来,非常重要的一步就是,药物治疗,因为现在我们已经了解了许多分子层面的属性。特别是在科学层面,展望未来,谨慎思考一些也许是很有趣的新应用,如干细胞治疗就是非常好的。抑或是应用日趋复杂的光遗传学技术,赋予下游其他细胞感光和传递光能信息至大脑的功能。

  <International Ophthalmology Times>:Can you give us a thumbnail sketch of what’s new as far as the knowledge of visual signaling pathways in recent years?

  《国际眼科时讯》:您能否大致讲述近几年视觉信号通路研究的新动向呢?

  Dr. Arshavsky:One interesting aspect, visual signaling is a very mature field and it was extremely well developed over the past 30 years or so. So, there are a couple of questions which are still remaining, not very well understood, one of which is what is the difference between rods and cones, and what are the entire complement of mechanisms in cones which allow them to never be blinded by light, which is very different from rods which are getting blind and saturated by light at a very high illumination levels.

  Another interesting question somehow relates to my work. We studied for a number of years now this very interesting phenomenon in which several signaling proteins undergo massive translocation between the different compartments of the photoreceptor cells between the outer segment which is a light sensitive and the rest of the photoreceptor. So they could translucent , arrest, recovering in  more recently this protein Grb14 which may be connected with insulin signaling.

  We understand quite a few aspects which are more signaling aspects of this protein translocation process, but we are still pretty much puzzled whether this process in reality plays more important neuroprotective role by changing the composition of the outer segment and inner segment of photoreceptor cells dependent on a level of ambient light.

  Arshavsky医生:很有趣的一点是,视觉信号通路已经是一个非常成熟的领域,在过去三十年里发展得很好。但仍然有一些尚未阐明、亟待解决的问题,其中之一是视杆和视锥细胞之间的区别是什么,强光照明为什么会导致视杆细胞失明和饱和,而视锥细胞不会被光照致盲,这一完整代偿机制在视锥细胞中是如何运行的。

  另一个有趣的问题在某种程度上与我目前的工作相关。数年来,我们一直在研究一个非常有趣的现象,一些信号蛋白在感光细胞不同区域,即对光敏感的外节部分,及其它感光细胞之间发生广泛易位。所以他们可能在Grb14蛋白中半透明、阻滞或者再生。最近发现Grb14蛋白可能与胰岛素信号通路有关。

  我们对于信号转导中的蛋白易位已经有了许多认识,但该过程能否通过依赖环境光来改变感光细胞外节和内节的组成呢,实际上这是否发挥着重要的神经保护作用呢,我们对此仍然非常困惑。

  <International Ophthalmology Times>:Could you give us a brief introduction about how GTPase functions in phototransduction?

  《国际眼科时讯》:您能否简要介绍GTP酶在光传导中的作用吗?

  Dr. Arshavsky:This is very simple. GTPase is actually enzymatic activity of this protein called transducin which is very central to our vision which acts as a molecular switch oscillating from an activated form bound to a molecule called GTP to inactive form bound to the molecule called GDP.

  So the difference is that when this GTP-bound form of transducin exists, then we see light and when GTP is transformed into GDP by this GTPase activity, we don’t see light anymore. The most important aspect why we need this GTPase is that it endows us with this ability not to see afterimages, not to have slow vision, but make our vision very apparition, very perky, so we can see one object after another because through this mechanism of GTPase, we essentially recharge the protein machinery in our photoreceptor cells to see the next image.

  Arshavsky医生:简而言之,GTP酶实际上是活化的转导蛋白,后者对于我们的视觉功能非常关键。它就像一个分子开关,结合GTP分子成为活化态,而结合GDP分子后就失活。

  不同的是,当这一GTP结合形式的转导蛋白存在时,眼睛能够感光,在GTP酶的作用下GTP转化为GDP,眼睛就不能感光了。为什么我们需要GTP酶呢?关键是它让残像消失,不引起视觉缓慢,让我们的视觉更迅速灵活,所以能够看完一个物体后又接着看另一个,这都是通过GTP酶这一机制来实现的,我们必须给感光细胞中的这架蛋白质机器“充电”,才能看下一帧。

  <International Ophthalmology Times>:Yesterday in your talk, you had the letter E on the screen stagnate and you presume everybody can see that, but some people couldn’t see it when you put the letter E in motion. Is that what you are talking about where the photoreceptor cells need to become active in being able to follow that letter E across the screen?

  《国际眼科时讯》:在您昨天的演讲中,您将字母E显示在屏幕上,假定在场每一位都能看到,而当字母E运动起来时,有些人就看不到了。想请问这就是您所提到的感光细胞需要活化才能注视屏幕上运动着的字母E吗?

  Dr. Arshavsky:In a nutshell, yes. In fact, the question is very interesting because all of us, no matter how fast is our GTPase, would not have an ability to see that letter if it moves too rapidly. For example if the bullet is flying in front of our face, we do not see this trace of the bullet. We actually see nothing. So what happens with these people with impaired GTPase is not that they are so different from us in the sense that they do not see too rapidly moving objects.

  But what the difference is that for them, objects which are moving slow enough which most people can see, they cannot see them because their photoreceptor cells are so slow. For them it’s the same as for us to see a flying bullet, to not to see the bullet which is running in front of our face. A little bit cruel analogy.

  Arshavsky医生:简而言之,是的。其实这也是个非常有趣的问题。当字母运动得飞快时,无论我们所有人的GTP酶反应速度有多快,其实都没法看到。例如,子弹飞到我们眼前时,是看不到子弹的运动轨迹的。我们什么也看不到。所以从观看高速运动的物体方面来看,GTP酶受损的人与我们所见的世界无差别,都看不到高速移动的物体。

  但不同的是,当物体移动速度足够慢而且大多数人也能看到时,他们却不能看到,因为感光细胞反应缓慢。对他们而言,看到飞行的子弹和看不到眼前的子弹其实没有差别。这比喻有点残酷了。

  <International Ophthalmology Times>:Could the GTPase be improved enough to someday see the flying bullet?

  《国际眼科时讯》:那么GTP酶会不会终有一天进化到能看到飞行的子弹呢?

  Dr. Arshavsky:You can do it in the mouse. And Ted also in fact was showing some of the data in a very important paper - for which Marie Burns was given Cogan Award several years ago - in which they were able to over express these GTPase complex in photoreceptors. And these photoreceptors became distinctly more fast, though I cannot tell you about the bullet but certainly these mice could have seen the letter moving more rapidly than otherwise they could see. Now, of course, the only way I can see about that is some sort of gene therapy for it is too minor improvement to take a risk in the foreseeable future.

  Arshavsky医生:你可以在大鼠身上做到这一点。有一篇很重要的文献,几年前Marie Burns就是因此获得了Cogan奖。Ted和她一起进行了感光细胞中GTP酶复合体过表达的试验。尽管我没法告诉你子弹这个问题的答案,但是这些感光细胞明显反应加快,当然实验鼠也能看到移动得更快的字母。当然,目前我唯一确定的是,在可预见的未来,相对于那些伴随风险,某些基因治疗只能轻微改善病情。

  <International Ophthalmology Times>:What are the challenges in studying the GTPase that you faced as a research scientist?

  《国际眼科时讯》:作为一名研究型学者,您在GTP酶研究中遇到了哪些挑战?

  Dr. Arshavsky:What I need to say first is the mechanism which we discussed last night is extremely universal. Every cell in our body has proteins which are relatives of transducin which has this GTPase activity as well. For example, when we are regulating our blood pressure, we do it through beta adrenergic receptor which is binding adrenalin and which is activating proteins very similar to transducin which also have GTPase. For instance when you are asking me a question taking a little bit of guard, then my adrenalin goes up. The truth of the matter is a very similar molecular pathway is now working my heart and blood vessels, very interesting.

  However, almost all pharmaceutical agents, which are used to regulate our blood pressure are working on the level of receptors themselves upstream from the GTPase. There were significant efforts in pharmaceutical industry particularly when these regulators of GTPase were discovered to build pharmaceutical programs around regulating, fine tuning GTPase activity. For instance you would be able to regulate the blood pressure by now targeting molecules downstream from the receptors, and it might have many different advantages. For instance if certain therapy stops working because adaptation takes place, you can use different target and you can start all over with the same patient.

  Till now it’s extraordinary difficult process because these molecules are acting inside the cells and because so far there is no efficient small molecules which can regulate GTPase activity. But from what I know, there are still a few efforts perhaps no less as vigorous efforts as in the late 90s when this protein family was discovered. People are not yet giving up to try to use this GTPase as a therapeutic target which would regulate the intensity and the timing of very different signaling pathways in our bodies.

  Arshavsky医生:首先我想说的是,我们昨晚探讨的机制问题,是非常具有普遍性的。我们身体里的每一个细胞中都有类似于转导蛋白这样具有GTP酶活性的蛋白质存在。例如,血压调节时,β肾上腺素受体会结合肾上腺素,激活其他具有GTP酶活性的蛋白质。又比方说,你向我提问,我就会采取些许防御措施,我身体中的肾上腺素就升高了。事实真相就是如此,我的心脏和血管正在受到相似的分子途径调节,非常有趣。

  但是,几乎所有用于调节血压的药物都作用于GTP酶上游的受体。制药行业在这方面费尽心思,当GTP酶调节剂被发现后,其被用于多项药物研究项目,包括GTP酶活性的调控或者微调。比方说,通过靶向定位受体下游分子,就能调节血压,可能还有更多其他优势。再比方说,某些治疗因发生药物适应而无效,可以采用不同靶点,然后又重新开始治疗。

  目前这仍然是一个艰苦卓绝的过程。因为细胞内分子的相互作用,目前为止没有发现任何调节GTP酶活性的小分子。但是据我所知,还是有一些努力没有白费,就在上世纪九十年代后期,发现了这种蛋白质家族。人们还没有放弃将GTP酶应用为治疗靶点这一想法,希望将来能够调节人体内各种不同信号通路的强度和时间。

  <International Ophthalmology Times>:Dr. Arshavsky, thank you very much.

  Arshavsky医生:非常感谢。

  Dr. Arshavsky:Thank you. My pleasure.

  Arshavsky医生:这是我的荣幸,谢谢。


 
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