Key to heart failure: New therapies on horizon

Mar. 5, 2013 ? 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 treat 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, "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 ONE. 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. Once calcium and calmodulin deliver GRK5 to the nucleus, the enzyme usurps 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 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 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 family, 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 nucleus.

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 on GRK5 were mutated was 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 obtained 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, 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."

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, 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 the 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."

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Story Source:

The above story is reprinted from materials provided by Temple University Health System, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Jessica I. Gold, Jeffrey S. Martini, Jonathan Hullmann, Erhe Gao, J. Kurt Chuprun, Linda Lee, Douglas G. Tilley, Joseph E. Rabinowitz, Julie Bossuyt, Donald M. Bers, Walter J. Koch. Nuclear Translocation of Cardiac G Protein-Coupled Receptor Kinase 5 Downstream of Select Gq-Activating Hypertrophic Ligands Is a Calmodulin-Dependent Process. PLoS ONE, 2013; 8 (3): e57324 DOI: 10.1371/journal.pone.0057324

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Source: http://feeds.sciencedaily.com/~r/sciencedaily/~3/ro7vXNjnLys/130305174655.htm

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Senator Seeks More Data Rights for Online Consumers

Before his planned retirement from Congress at the end of next year, Senator John D. Rockefeller IV, the West Virginia Democrat, intends to give American consumers more meaningful control over personal data collected about them online.

To that end, Mr. Rockefeller on Thursday introduced a bill called the ?Do-Not-Track Online Act of 2013.?

The bill would require the Federal Trade Commission to establish standardized mechanisms for people to use their Internet browsers to tell Web sites, advertising networks, data brokers and other online entities whether or not they were willing to submit to data-mining.

The bill would also require the F.T.C. to develop rules to prohibit online services from amassing personal details about users who had opted out of such tracking.

Mr. Rockefeller proposed the same bill two years ago. But he did not push it in the Senate at the time because industry groups had pledged to voluntarily develop systems to honor the browser-based don?t-track-me flags. Last year, however, negotiations between industry groups and consumer advocates over how to execute these mechanisms essentially broke down and have since made little progress.

The new Rockefeller bill indicates that the senator believes the industry has not acted in good faith.

?The privacy of Americans is increasingly under assault as more and more of their daily lives are conducted online,? Mr. Rockefeller, the chairman of the Senate Committee on Commerce, Science and Transportation, wrote on Thursday in an e-mail sent to a reporter. ?Industry made a public pledge to develop do-not-track standards that will truly protect consumer privacy ? and it has failed to live up to that commitment. They have dragged their feet long enough.?

Industry representatives said that legislation was unnecessary because advertising networks and data brokers several years ago voluntarily introduced their own opt-out program for consumers, called Your AdChoices. Unlike the Do Not Track signals which would allow users to make a one-time decision about all online tracking from their own browsers, the industry program requires people to go to a site and individually select the companies, among several hundred, from whom they prefer not to receive marketing offers based on data-mining.

Stuart Ingis, a lawyer for the Digital Advertising Alliance, an industry consortium, said the program, which involves consumers installing individual cookies on their browsers, demonstrates that users already have choices about data collection.

?It?s a lot easier to use a system that is already built and works,? Mr. Ingis said.

Over the last few years, the number of companies that collect information about the reading habits, health concerns, financial capacity, search queries, purchasing patterns and other activities of online consumers has skyrocketed. Industry representatives argue that this benefits people because it enables companies to show them relevant ads, and that the ads themselves finance online sites and services that are free to consumers. Moreover, they say, the data collection is ?anonymous? because online services typically use numerical customer codes, not real names or e-mail addresses, to track the behavior of individuals.

But consumer advocates warn that such profiling systems, which can collect thousands of details on nearly every adult in the United States, can be used to segment some people for preferential offers while relegating others to inferior treatment. Despite industry claims that online tracking is anonymous, a few computer scientists have reported that sites often leak information that can identify individuals, including names, addresses and other details, to third parties.

?Nowadays, there is an incredible proliferation of tracking,? said Dan Auerbach, a staff technologist at the Electronic Frontier Foundation, a digital rights group in San Francisco. ?Data brokers, companies that you never heard of, are collecting massive dossiers about you as you browse around the Web and, right now, there are no limitations on the collection or use of those dossiers.?

To give people greater control over their own surveillance online, the Federal Trade Commission in a report on consumer privacy last March urged industry groups to adopt Do Not Track mechanisms by the end of 2012. In fact, the major browsers ? Firefox from Mozilla, Google?s Chrome, and the more recent iterations of Internet Explorer ? already offer the don?t-track-me buttons. When these options are turned on, they send out signals to sites, and third parties like ad networks operating on those sites, that certain users do not want to have their information collected.

But industry groups and consumer advocates have been at odds for more than a year over how ?Do Not Track? mechanisms should be presented to users and how online services should respond to the signals. In the absence of legislation or industry consensus, companies are free to ignore those user preferences.

Some browsers have responded to this standstill by taking matters into their own hands and blocking third-party tracking cookies, as my colleague Somini Sengupta reported this week.

But Mr. Rockefeller?s bill indicates that legislative action could pre-empt voluntary industry measures.

?This is a signal that Senator Rockefeller is serious about getting Do Not Track done,? said David C. Vladeck, a professor at Georgetown Law. Until last month, Mr. Vladeck served as director of the bureau of consumer protection at the F.T.C. ?I think industry writ large ? browser companies, advertising networks, data brokers ? are going to understand that he is serious about getting across the finish line.?

Source: http://bits.blogs.nytimes.com/2013/02/28/senator-seeks-more-data-rights-for-online-consumers/

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