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UW metabolism researchers blaze new paths

As a human health issue, most people think about metabolism in the context of calories in/calories out, energy consumption and body weight. But lately, scientists are finding far more sweeping health implications for this biological process.

With metabolic pathways now seen as essential players in human development and aging, as well as common diseases such as cancer, diabetes and Alzheimer’s, metabolism has become a wellspring of new knowledge for biologists.

In terms of excitement and possibilities, the field today could fairly be compared to stem cell research 15 years ago, or recombinant DNA research a few decades ago. Often called the “chemistry of life,” metabolism provides the biochemical building blocks for cell growth, development and death, but there are still huge gaps in understanding.

ATase structure
This enzyme identified by Luigi Puglielli, associate professor of medicine, plays a role in the molecular degeneration that takes place in Alzheimer’s disease. Puglielli is developing compounds that could help block Alzheimer’s.

The renaissance can be seen at the University of Wisconsin-Madison, where an estimated 100-plus scientists are studying core aspects of metabolism, and many others have some peripheral connection. It’s the impetus for a new initiative led by the Morgridge Institute for Research (MIR) to provide leadership, infrastructure and community building in the field. (See related story.)

“The field is really cooking right now,” says Alan Attie, professor of biochemistry who studies metabolic issues in Type 2 diabetes. “We’re taking topics that were thought to be kind of worn-out and old-fashioned, dusting them off and realizing there is way more to it than anyone imagined.”

Biochemistry Professor Dave Pagliarini says only a decade ago, metabolism was “relegated to memorizing the canonical pathways in cells,” and seen as something already known and defined. Now scientists are discovering new metabolites and pathways — and disproving old ones — all the time.

“As new tools gave us new insights,” Pagliarini says, “it became clear and in retrospect should have been obvious that most diseases have at their core metabolic defects.”

UW-Madison’s metabolism research environment is diverse, with active projects at the clinical, bench and computational levels. Here is a snapshot of two metabolism scientists from CALS. Three more snapshots are included in the original article, posted here on the MIR website.

Dave Pagliarini: Revisiting mitochondria, the cellular powerhouse

Pagliarini stumbled into studying mitochondria as a graduate student, when he found a protein that unexpectedly localized in mitochondria. Despite decades of intensive study and multiple Nobel Prizes awarded for mitochondria discoveries, there remain many unknowns — including about 250 mitochondrial proteins that have no established function.

“If your car breaks down and you pop the hood and a quarter of the parts have no meaning, you’re not likely to solve the problem,” he says.

Pagliarini
Pagliarini

“What we do in our laboratory is try to find systematic ways to annotate those parts and proteins — what do they do, what are their biochemical roles, and how do mutations give rise to human diseases. I want to fundamentally understand how these metabolic hubs operate.”

Mitochondria produce 90 percent of adenosine triphosphate, or ATP, the chemical currency of our bodies. It uses 90 percent of the oxygen we breathe to make ATP. The “cellular powerhouse” role is well-established, but mitochondria also play a role in more than 150 diseases, from rare inborn disorders to Parkinson’s, diabetes and cancer.

Because mitochondria are double-membrane entities within the cell, they offer both therapeutic challenges and opportunities. While difficult to get therapeutic targets past this extra barricade, the fact that it’s a stand-alone entity might make therapies more precise. For now, Pagliarini says there are no effective treatments for mitochondrial disorders but there are major initiatives under way, and a better “systems level” understanding will contribute to their success.

Alan Attie: The genetics of Type 2 diabetes

Attie studies Type 2 diabetes, where people develop resistance to insulin and cannot compensate with higher insulin levels. The most common cause in humans is obesity. About 80 percent of all people with Type 2 diabetes are obese, yet the majority of obese people are not diabetic.

Says Attie: “We look at this dichotomy from a genetic point of view and ask: What are the genes that determine whether or not an obese animal will develop diabetes?”

Attie
Attie

Attie developed a highly diverse model strain of mice that have all the traits necessary to study this question – one group that is diabetic when obese, and one that is not. And they have identified and mapped a number of genes that contribute to diabetes.

“These mice strains contain as much genetic diversity as the entire human population, so it’s a very nice genetic resource to look for variations in genes that contribute to diabetes-related phenotypes,” Attie says.

Attie says this mouse population could be a campus resource for many types of disease models, including heart disease, cancer and infectious disease. “It’s all where you shine the light.”

Read the full story on the MIR website here

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