科普知識(shí)學(xué)英語研究人員發(fā)現(xiàn)導(dǎo)致心力衰竭的關(guān)鍵因素

1、.Some 5.8 million Americans suffer from heart failure, a currently incurable disease. But scientists at Temple University School of Medicine's TUSM Center for Translational Medicine have discovered a key biochemical step underlying the condition that could aid the development of new drugs to tre

2、at and 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, &q

3、uot;The more we learn about the disease mechanism, the more drug targets we'll 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 O

4、NE. The report is the first to show that an enzyme called GRK5 G-protein coupled receptor kinase 5 can gain access to a heart cell's nucleus - its command center, where control of its genes is maintained - by way of a transport mechanism involving calcium and a protein known as calmodulin鈣調(diào)

5、蛋白. Once calcium and calmodulin deliver GRK5 to the nucleus, the enzyme usurps奪取 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 p

6、layer in maladaptive cardiac hypertrophy, which is the end stage of heart failure, when the heart muscle becomes enlarged and unable to pump enough blood to keep vital organs functioning. While GRK5's ability to get inside the nucleus was known, Koch and colleagues worked to fill in the missing

7、links in its transport mechanism. Those links, they hope, will not only allow them to better understand GRK5's 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 fami

8、ly, owing to its presence in the nucleus. Its journey begins at the cell membrane, 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 nu

9、cleus. The team found that GRK5's transport requires calmodulin after examining different places on the enzyme where various escort molecules attach. They then introduced mutations that altered the attachment sites. Only when calmodulin-binding residues剩余物 on GRK5 were mutated was

10、 the enzyme prevented from reaching the nucleus. Those mutations led to dramatic decreases in nuclear GRK5 levels and corresponding declines in the activity of genes known to drive cardiac hypertrophy. Calmodulin's ability to bind to GRK5 is in turn dependent on calcium. The same results were ob

11、tained both in vitro, using human heart muscle cells cultivated under laboratory conditions, and in vivo, in mice. The team's research also marks a breakthrough in scientists' understanding of the role of neurohormones in hypertrophy. Released by specialized neurons into the bloodstream

12、, neurohormones have long been cited as a cause of heart cell enlargement. "One of the novel findings to fall out of this paper is that not all hypertrophic signals from neurohormones are the same," Koch explained. "That's something to keep in mind as we move forward."&#

13、160;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 cardiac GRK, GRK2," he said. He cautioned, however, that trials in patients with GRK5 inhibition are years away. First,

14、agents capable of blocking GRK5 transport must be identified and tested in animals. The work is an important advance for Temple's Center for Translational Medicine. GRK5 enters the pipeline of novel drug targets under investigation by the Center's scientists and clinicians, who share th

15、e common goal of coordinating clinical practice and basic research to speed the delivery of new therapies to patients. "It's another entry into larger, pre-clinical animal studies," Koch said. "Something new to start down the path of translational medicine."約達(dá)580萬美國人患有心臟

16、衰竭，目前無法治愈的疾病。但在坦普爾大學(xué)醫(yī)學(xué)院的TUSM轉(zhuǎn)化醫(yī)學(xué)中心的科學(xué)家們發(fā)現(xiàn)了一個(gè)關(guān)鍵的根本條件，可以幫助開發(fā)新的藥物來治療，并可能防止它的生化步驟?！拔覀兡壳笆褂玫男呐K衰竭的藥物都不是很有效的，解釋說：首席研究員沃爾特·科赫博士，藥理學(xué)教研室教授兼TUSM，在TUSM轉(zhuǎn)化醫(yī)學(xué)研究中心主任。但是，他補(bǔ)充說，“我們更理解疾病的機(jī)制，我們會(huì)發(fā)現(xiàn)更多的藥物靶標(biāo)。 這是什么Koch和他的同事們?cè)谕旭R斯·杰斐遜大學(xué)和加州大學(xué)戴維斯分校，實(shí)現(xiàn)了在其最新的研究中，出如今3月5日出版的在線期刊PLoS ONE。該報(bào)告是說明一種酶叫做GRK5G-蛋白偶聯(lián)受體激酶5可以訪問到心

17、臟細(xì)胞的細(xì)胞核-指揮中心，保持其基因控制-方式傳輸機(jī)制涉及鈣離子和鈣調(diào)蛋白的蛋白質(zhì)被稱為鈣調(diào)蛋白。一旦鈣和鈣調(diào)蛋白提供GRK5到細(xì)胞核，酶篡奪奪取控制特定基因，最終導(dǎo)致肥大，心臟細(xì)胞生長在規(guī)模較大。肥大是心臟衰竭的生物標(biāo)志。 GRK5此前被確定為一個(gè)關(guān)鍵球員在適應(yīng)不良的心肌肥厚，這是終末期心臟衰竭，心臟肌肉變得擴(kuò)大，不能泵出足夠的血液，以保持重要器官運(yùn)作時(shí)。雖然GRK5的才能得到細(xì)胞核內(nèi)是眾所周知的，科赫和他的同事們的工作，以填補(bǔ)其傳輸機(jī)制的缺失環(huán)節(jié)。他們希望，這些鏈接，不僅可以讓他們更好地理解GRK5的作用導(dǎo)致心臟細(xì)胞的大小增加，但也想方設(shè)法阻止這個(gè)過程中，更有效地治療心臟衰竭。&

18、#160;GRK5的酶GRK家族成員是一個(gè)獨(dú)特的，由于它的存在，在細(xì)胞核中。開場(chǎng)的行程中，其中接收的信號(hào)Gq蛋白偶聯(lián)型受體作為提示“護(hù)送在細(xì)胞外表分子在細(xì)胞膜 - 其中之一是鈣調(diào)蛋白，作為研究人員發(fā)現(xiàn) - 附加到單次給予，并引導(dǎo)它到細(xì)胞核。 該研究小組發(fā)現(xiàn)，鈣調(diào)素研究不同的地方后，對(duì)酶的各種護(hù)送分子附著，GRK5的交通需要。然后，他們介紹了突變，改變了附著點(diǎn)。只有當(dāng)上GRK5的鈣調(diào)蛋白結(jié)合的殘基剩余物突變是酶無法到達(dá)細(xì)胞核。這些突變導(dǎo)致大幅度降低核GRK5的程度和相應(yīng)的驅(qū)動(dòng)心肌肥厚的基因的活性下降。鈣調(diào)蛋白的結(jié)合才能GRK5是反過來又依賴于鈣。得到同樣的結(jié)果，無論是在體外，在實(shí)驗(yàn)室條件下培養(yǎng)人的心臟肌肉細(xì)胞，在體內(nèi)，在小鼠。 該小組的研究也標(biāo)志著科學(xué)家理解神經(jīng)激素的作用，肥大的打破。由專門的神經(jīng)元釋放進(jìn)入血液，神經(jīng)激素早就被引用作為心臟細(xì)胞腫大的原因。 “掉出本文的新發(fā)現(xiàn)之一是，并非所有的肥厚性神經(jīng)激素的信號(hào)是一樣的，科赫解釋?！斑@件事情要記住，作為我們前進(jìn)。 下一步，根據(jù)科克，以測(cè)試不同的代理