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1、Some 5.8 million Americans suffer from heart failure, a currently incurable disease. But scientists at Temple University School of Medicines (TUSM) Center for Translational Medicine have discovered a key biochemical step underlying the condition that could aid the development of new drugs to treat a
2、nd possibly prevent it. Drugs we currently use for heart failure are not very effective, explained lead investigator Walter J. Koch, PhD, Professor and Chairman of the Department of Pharmacology at TUSM, and Director of the Center for Translational Medicine at TUSM. But, he added, The more we learn
3、about the disease mechanism, the more drug targets well find.That is what Koch and colleagues at Thomas Jefferson University and the University of California, Davis, achieved in their latest study, which appears in the March 5 issue of the online journal PLOS ONE. The report is the first to show tha
4、t an enzyme called GRK5 (G-protein coupled receptor kinase 5) can gain access to a heart cells nucleus - its command center, where control of its genes is maintained - by way of a transport mechanism involving calcium and a protein known ascalmodulin（钙调蛋白）. Once calcium and calmodulin deliver GRK5 t
5、o the nucleus, the enzymeusurps（夺取）control over specific genes, ultimately causing hypertrophy, in which heart cells grow larger in size. Hypertrophy is a biological hallmark of heart failure.GRK5 had previously been identified as a key player in maladaptive cardiac hypertrophy, which is the end sta
6、ge of heart failure, when the heart muscle becomes enlarged and unable to pump enough blood to keep vital organs functioning. While GRK5s ability to get inside the nucleus was known, Koch and colleagues worked to fill in the missing links in its transport mechanism. Those links, they hope, will not
7、only allow them to better understand GRK5s role in causing heart cells to increase in size but also find ways to block that process to more effectively treat heart failure.The GRK5 enzyme is a unique member of the GRK family, owing to its presence in the nucleus. Its journey begins at the cell membr
8、ane, where signals received by a molecule at the cell surface known as a Gq-coupled receptor prompt escorts - one of which is calmodulin, as the researchers discovered - to attach to GRK5 and guide it to the nucleus.The team found that GRK5s transport requires calmodulin after examining different pl
9、aces on the enzyme where various escort molecules attach. They then introduced mutations that altered the attachment sites. Only when calmodulin-bindingresidues（剩余物）on GRK5 were mutated was the enzyme prevented from reaching the nucleus. Those mutations led to dramatic decreases in nuclear GRK5 leve
10、ls and corresponding declines in the activity of genes known to drive cardiac hypertrophy. Calmodulins ability to bind to GRK5 is in turn dependent on calcium. The same results were obtained both in vitro, using human heart muscle cells cultivated under laboratory conditions, and in vivo, in mice.Th
11、e teams research also marks a breakthrough in scientists understanding of the role of neurohormones in hypertrophy. Released by specialized neurons into the bloodstream, neurohormones have long been cited as a cause of heart cell enlargement.One of the novel findings to fall out of this paper is tha
12、t not all hypertrophic signals from neurohormones are the same, Koch explained. Thats something to keep in mind as we move forward.The next step, according to Koch, is to test the ability of different agents to keep GRK5 out of the nucleus. We are now discussing a trial on inhibition of another card
13、iac GRK, GRK2, he said. He cautioned, however, that trials in patients with GRK5 inhibition are years away. First, agents capable of blocking GRK5 transport must be identified and tested in animals.The work is an important advance for Temples Center for Translational Medicine. GRK5 enters the pipeli
14、ne of novel drug targets under investigation by the Centers scientists and clinicians, who share the common goal of coordinating clinical practice and basic research to speed the delivery of new therapies to patients.Its another entry into larger, pre-clinical animal studies, Koch said. Something ne
15、w to start down the path of translational medicine.约达580万美国人患有心脏衰竭，目前无法治愈的疾病。但在坦普尔大学医学院的（TUSM）转化医学中心的科学家们发现了一个关键的基本条件，可以帮助开发新的药物来治疗，并可能防止它的生化步骤。“我们目前使用的心脏衰竭的药物都不是很有效的，解释说：”首席研究员沃尔特科赫博士，药理学教研室教授兼TUSM，在TUSM转化医学研究中心主任。但是，他补充说，“我们更了解疾病的机制，我们会发现更多的药物靶标。”这是什么Koch和他的同事们在托马斯杰斐逊大学和加州大学戴维斯分校，实现了在其最新的研究中，出现在3月
16、5日出版的在线期刊PLoS ONE。该报告是表明一种酶叫做GRK5（G-蛋白偶联受体激酶5）能够访问到心脏细胞的细胞核-指挥中心，保持其基因控制-方式传输机制涉及钙离子和钙调蛋白的蛋白质被称为（钙调蛋白）。一旦钙和钙调蛋白提供GRK5到细胞核，酶篡夺（夺取）控制特定基因，最终导致肥大，心脏细胞生长在规模较大。肥大是心脏衰竭的生物标志。GRK5此前被确定为一个关键球员在适应不良的心肌肥厚，这是终末期心脏衰竭，心脏肌肉变得扩大，不能泵出足够的血液，以保持重要器官运作时。虽然GRK5的能力得到细胞核内是众所周知的，科赫和他的同事们的工作，以填补其传输机制的缺失环节。他们希望，这些链接，不仅可以让他们更好地了解GRK5的作用导致心脏细胞的大小增加，但也想方设法阻止这个过程中，更有效地治疗心脏衰竭。GRK5的酶GRK家族成员是一个独特的，由于它的存在，在细胞核中。开始的行
