2009 July 02 Thursday
Wnt Pathway Manipulation Key For MS Myelin Sheath Repair

Even if you do not have multiple sclerosis (MS) or know anyone who has MS the research into how to repair myelin sheath (nerve insulation which gets damaged in MS) matters for your own brain's future. As we age our myelin sheath degrades and this contributes to cognitive decline experienced as people get older. Therefore I always cheer on MS research more than research in most diseases. Work at USCF and U Cambridge put to a regulatory pathway as key for telling oligodendrocyte cells to make more myelin.

In this study the researchers have identified the Wnt pathway, which plays an active role in the maintenance and proliferation of stem cells, as a crucial determinant of whether oligodendrocytes can efficiently make myelin. Their studies demonstrate that if the Wnt pathway is abnormally active, then the process is inhibited. This opens up the exciting possibility that the repair can be enhanced in MS patients by drugs that block the Wnt pathway.

Professor Robin Franklin from the University of Cambridge, a co-senior author of the study, explained the significance of their findings: "The pathway we identified plays a critical role in whether repair to the damaged cells will or will not occur. Interestingly, mutations in this particular pathway are also involved in several cancers. In this regard, drugs that inhibit this pathway from signaling have been sought which might suppress tumour growth. These same drugs may also find a role in promoting repair in MS."

Regulatory pathways that control growth are always of interest to cancer researchers. So cancer research work has helped build up information about the Wnt regulatory pathway that helps MS researchers in their own investigations. More generally, cancer research into cell growth regulation helps to build up the knowledge we need to develop a large assortment of cell therapies.

Gene chips which allow fast measurement of activity of large numbers of genes made this research possible.

To find out which genes were contributing to three key stages in the repair process – the recruitment of oligodendrocyte precursors to the site of injury, the maturation of those cells into functional oligodendrocytes, and the formation of a new myelin sheath -- they measured the activity of 1,040 genes. All of the genes they studied encode transcription factors, which regulate the activity of other genes. Their experiments showed that 50 transcription factors are working during key steps in myelin repair.

One of the reasons I expect a revolution in biomedical treatments over the next 20 years is the development of chips that can do massively parallel manipulations and measures with cells and cellular components. Biotechnology now benefits from the same shrinking of scale that has done so much to double computer power many times.

The researchers were able to focus on a single gene that might make a good target for drug development.

The team then honed in on a gene called Tcf4, because its expression was strong in damaged areas where repair attempts were under way.

Tcf4 is involved in a cascade of biochemical events known as the Wnt (pronounced "wint") pathway, whose importance has been well recognized in normal development of many tissues, including the brain. Until now, however, Wnt had not been linked to myelin production or repair.

"This is the first evidence implicating the Wnt pathway in multiple sclerosis," says lead author Stephen P.J. Fancy, PhD, a postdoctoral fellow in the Rowitch lab. "We consider this an exciting development in our efforts to understand why the repair process often fails in the disease."

Some of us alive today will live long enough to see tissue repair to become commonplace throughout the body. Development of this capability will slow and eventually reverse the aging process.

By Randall Parker    2009 July 02 12:15 PM   Entry Permalink | Comments (1)
2009 April 08 Wednesday
Nerves Grown From Brain To Spinal Cord In Rats

One step closer to repairing crippling spinal cord injuries.

For the first time, researchers have clearly shown regeneration of a critical type of nerve fiber that travels between the brain and the spinal cord and which is required for voluntary movement. The regeneration was accomplished in a brain injury site in rats by scientists at the University of California, San Diego School of Medicine and is described in a study to be published in the April 6th early on-line edition of the Proceedings of the National Academy of Sciences (PNAS).

“This finding establishes a method for regenerating a system of nerve fibers called corticospinal motor axons. Restoring these axons is an essential step in one day enabling patients to regain voluntary movement after spinal cord injury,” said Mark Tuszynski, MD, PhD, professor of neurosciences, director of the Center for Neural Repair at UC San Diego and neurologist at the Veterans Affairs San Diego Health System.

Most of us are going to live to see the day when tissue engineering biotechnologies make it possible to repair types of damage that we now must live with. Got very worn joints? Damaged tendons that won't heal? Damaged vocal cords? Nerve damage in an extremity? All this stuff is going to become repairable.

Genetic engineering made this possible.

The UC San Diego team achieved corticospinal regeneration by genetically engineering the injured neurons to over-express receptors for a type of nervous system growth factor called brain-derived neurotrophic factor (BDNF). The growth factor was delivered to a brain lesion site in injured rats. There, the axons – because they now expressed trkB, the receptor for BDNF– were able to respond to the growth factor and regenerate into the injury site. In the absence of overexpression of trkB, no regeneration occurred.

Although functional recovery in the animals was not assessed, the new study shows for the first time that regeneration of the corticospinal system – which normally does not respond to treatment – can be achieved in a brain lesion site.

Scientists will continue to find ways to improve genetic engineering techniques. Cells will therefore become more controllable. Humans will become repairable just like cars.

By Randall Parker    2009 April 08 10:27 PM   Entry Permalink | Comments (0)
2008 November 06 Thursday
Gene Silencing Boosts Neuron Growth For Repair

By silencing genes that inhibit neural growth some scientists think they can create neurons that repair brain and spinal damage.

Boston, MA—Silencing natural growth inhibitors may make it possible to regenerate nerves damaged by brain or spinal cord injury, finds a study from Children's Hospital Boston. In a mouse study published in the November 7 issue of Science, researchers temporarily silenced genes that prevent mature neurons from regenerating, and caused them to recover and re-grow vigorously after damage.

Because injured neurons cannot regenerate, there is currently no treatment for spinal cord or brain injury, says Zhigang He, PhD, Associate Professor of Neurology at Children's and senior author on the paper. Previous studies that looked at removing inhibitory molecules from the neurons' environment, including some from He's own lab, have found only modest effects on nerve recovery. But now He's team, in collaboration with Mustafa Sahin, MD, PhD, Assistant Professor of Neurology at Children's, demonstrates that re-growth is primarily regulated from within the cells themselves.

"We knew that on completion of development, cells stop growing due to genetic mechanisms that prevent overgrowth," explains He. "We thought that this kind of mechanism might also prevent regeneration after injury."

Keep in mind that aging basically amounts to a slow accumulation of injury. The ability to make cells grow is also essential to the development of rejuvenation therapies. Brain rejuvenation is the hardest challenge for aging reversal therapies. So the development of techniques for turning on neuron growth has special importance.

By blocking inhibiting genes that suppress the mTOR pathway the scienists were able to boost brain repair in injured mice.

The key pathway for controlling cell growth in neurons, known as the mTOR pathway, is active in cells during development, but is substantially down-regulated once neurons have matured. Moreover, upon injury, this pathway is almost completely silenced, presumably for the cell to conserve energy to survive. He and colleagues reasoned that preventing this down-regulation might allow regeneration to occur.

He and his team used genetic techniques to delete two key inhibitory regulators of the mTOR pathway, known as PTEN and TSC1, in the brain cells of mice. After two weeks, the mice were subjected to mechanical damage of the optic nerve. Two weeks post-injury, up to 50 percent of injured neurons in the mice with gene deletions of PTEN or TSC1 survived, compared to about 20 percent of those without the deletions. And of the surviving mutant mice, up to 10 percent showed significant re-growth of axons, the fiber-like projections of neurons that transmit signals, over long distances. This re-growth increased over time.

By Randall Parker    2008 November 06 11:07 PM   Entry Permalink | Comments (0)
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