Strides made toward drug therapy for inherited kidney disease

ScienceDaily (Oct. 27, 2011) — Scientists at UC Santa Barbara have discovered that patients with an inherited kidney disease may be helped by a drug that is currently available for other uses. The findings are published in this week's issue of the Proceedings of the National Academy of Sciences.

Over 600,000 people in the U.S., and 12 million worldwide, are affected by the inherited kidney disease known as autosomal-dominant polycystic kidney disease (ADPKD). The disease is characterized by the proliferation of thousands of cysts that eventually debilitate the kidneys, causing kidney failure in half of all patients by the time they reach age 50. ADPKD is one of the leading causes of renal failure in the U.S.

"Currently, no treatment exists to prevent or slow cyst formation, and most ADPKD patients require kidney transplants or lifelong dialysis for survival," said Thomas Weimbs, director of the laboratory at UCSB where the discovery was made. Weimbs is an associate professor in the Department of Molecular, Cellular and Developmental Biology, and in the Neuroscience Research Institute at UCSB.

Recent work in the Weimbs laboratory has revealed a key difference between kidney cysts and normal kidney tissue. They found that the STAT6 signaling pathway -- previously thought to be mainly important in immune cells -- is activated in kidney cysts, while it is dormant in normal kidneys. Cystic kidney cells are locked in a state of continuous activation of this pathway, which leads to the excessive proliferation and cyst growth in ADPKD.

The drug Leflunomide, which is clinically approved for use in rheumatoid arthritis, has previously been shown to inhibit the STAT6 pathway in cells. Weimbs and his team found that Leflunomide is also highly effective in reducing kidney cyst growth in a mouse model of ADPKD.

"These results suggest that the STAT6 pathway is a promising drug target for possible future therapy of ADPKD," said Weimbs. "This possibility is particularly exciting because drugs that inhibit the STAT6 pathway already exist, or are in active development."

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The above story is reprinted from materials provided by University of California - Santa Barbara.

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Journal Reference:

E. E. Olsan, S. Mukherjee, B. Wulkersdorfer, J. M. Shillingford, A. J. Giovannone, G. Todorov, X. Song, Y. Pei, T. Weimbs. Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1111966108

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Step toward unraveling Alzheimer's disease

ScienceDaily (Oct. 27, 2011) — Scientists outline new methods for better understanding links between specific proteins and the risks associated with Alzheimer's disease in an article co-authored by University of Alabama researchers and publishing in Science Express.

In experiments using a series of model organisms, including yeast, microscopic roundworms and rats, the researchers show how basic mechanisms inside cells are disrupted when a specific human protein, known as the amyloid beta peptide, fails to properly fold. This study also shows the role a second protein, referred to by the scientists as PICALM, can play in modifying the problem.

"By using these yeast models, in combination with worms, we really are hopeful of finding a way by which we can understand and maybe combat Alzheimer's disease more rapidly," said Dr. Guy Caldwell, professor of biological sciences at The University of Alabama and one of three UA-authors on the Science article.

The research involved scientists from several universities and research institutes, including the Whitehead Institute and Massachusetts Institute of Technology, where the lead author, Dr. Sebastian Treusch, is affiliated. Treusch works in the lab of Dr. Susan Lindquist, a renowned expert in cell biology and collaborator with Caldwell on a grant from the Howard Hughes Medical Institute that funded part of this research.

While the repeated misfoldings of amyloid beta peptides within the human brain were previously known to trigger the death of neurons, resulting in Alzheimer's, Caldwell says the underlying mechanisms of toxicity weren't as well understood.

Properly functioning cells must efficiently deliver proteins and chemicals to other parts of the cell, Caldwell said. This research shows how the amyloid beta peptide interrupts a specific cellular pathway called endocytosis, preventing the delivery of other needed proteins to other parts of the cell.

"Understanding what is going wrong inside a cell, or what pathways or proteins might be directly linked to the mechanisms that are involved in Alzheimer's, is really a much more fruitful strategy for drug development."

Information drawn from the brains of deceased Alzheimer's patients, who previously donated their bodies to science, was also significant in the effort, Caldwell said.

Rapid advances in DNA sequencing methods and human genetic population studies are generating an overwhelming number of leads for researchers; those genetic studies, taken in combination with advantageous attributes of simple organisms, can reveal basic functions of genes and proteins and can be an insightful combination, Caldwell says.

"What this paper shows is that simple systems, like yeast and worms, can be engineered to discern mechanisms that might be associated with complex human diseases, and, by that, we may accelerate the path of discovery for advancing therapeutics for those diseases."

UA's lead author is Dr. Shusei Hamamichi, a former post-doctoral researcher in the Caldwell lab who earned his doctorate at UA while working alongside Caldwell and Dr. Kim Caldwell, also a co-author of the paper and an associate professor of biological sciences at UA.

In the paper's conclusion, the researchers describe the potential significance of the development in light of the challenges faced in understanding and treating Alzheimer's disease.

"The treatments available for AD are few and their efficacy limited," the scientists wrote. "Determining how best to rescue neuronal function in the context of the whole brain is a problem of staggering proportions."

"On a personal level," Caldwell said, "so many of us have been affected by family or loved ones who have suffered from Alzheimer's. It's a great privilege for us to be able to contribute to the respective avenues of our understanding of the disease. It's a devastating disorder. The societal cost of Alzheimer's disease is tremendous."

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The above story is reprinted from materials provided by University of Alabama in Tuscaloosa.

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Journal Reference:

Sebastian Treusch, Shusei Hamamichi, Jessica L. Goodman, Kent E. S. Matlack, Chee Yeun Chung, Valeriya Baru, Joshua M. Shulman, Antonio Parrado, Brooke J. Bevis, Julie S. Valastyan, Haesun Han, Malin Lindhagen-Persson, Eric M. Reiman, Denis A. Evans, David A. Bennett, Anders Olofsson, Philip L. Dejager, Rudolph E. Tanzi, Kim A. Caldwell, Guy A. Caldwell, Susan Lindquist. Functional Links Between Aß Toxicity, Endocytic Trafficking, and Alzheimer’s Disease Risk Factors in Yeast. Science, 2011; DOI: 10.1126/science.1213210

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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.

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