Ravi Bellamkonda

(Edited for clarity and to insert hyperlinks)

His lab is at Georgia Tech in Atlanta, going to talk about CSPG expression in the astroglial scar.  (CSPG stands for Chondroitin Sulfate Proteoglycan; it’s a kind of molecule that — among other things– causes scar formation and prevents axons from growing after SCI).

Lots of papers have been published that shows it inhibits neuronal growth after SCI.

At his lab they’re looking at CS-GAGs (sugars) . . . we have all sorts of tools now, but they only help if we understand the biology extremely well, so they looked at this question:

What is the contribution of CS-GAGs to CSPG-mediated inhibition? (From the Bellamkonda lab website, here’s the exact language:

Injury to the central nervous system induces production of glial scar, which prevents neuronal regeneration. Chondroitin sulfate proteoglycans (CSPGs), which are associated with the glial scar, are potent inhibitors of neuronal growth. CSPGs consist of a core protein to which are attached polysaccharide chains called glycosaminoglycans (GAGs). Each GAG chain is composed of a tetrasaccharide linking region that connects the core protein to the disaccharide repeats. Recent studies have shown that the degree of sulfation of these disaccharide repeats directly affects the extent of neuronal inhibition. Although sulfated GAGs are being implicated in neuronal inhibition, the cellular mechanisms by which these molecules inhibit regeneration are as yet poorly understood. Our research focuses on gaining a better understanding of the mechanism of CS-GAG-mediated neuronal inhibition.

When there’s an injury, the nature of the sugars changes — their molecular profile changes in such a way that they inhibit growth.

(fyi, this is a talk that would be great for a room full of grad students, which means it’s probably excellent, but not readily translatable)

Doing what I can . . . they know that sugars interfere with growth.  They can target the enzymes that make those sugars.  They did that in their lab in a very finely tuned way and created media that permits neuronal growth.

This matters because you now have a very, very specific target and aren’t compelled to use brute force.  They have a nanocarrier “straw” that can deliver the goods to the targets . . . a nano carrier is between 50 and 100 nanometers. (A sheet of ordinary paper is 100,000 nanometers thick, which means their biggest nano carrier is one one-thousandth of the thickness of a page in a book.)

Okay, ChABC (Chondroitinase ABC) is one of the things that works against the neuron-growth-hating CSPGs; the problem is that it’s thermally unstable and loses 90% of its activity in 2 – 4 days.  Given that the CSPGs are deposited over a period of 2-3 weeks after injury, you need repeat injections and maintain constant delivery of fresh agents.

They went looking for something to resolve that issue, and settled on a different sugar called Trehalose, which is a sugar from nature and a protein stabilizer.  Plants that grow in the desert have it . . . and you can use it to thermostabilize chABC.  It preserves the activity for four weeks.  Kind of genius, actually.  Now we have a stable enzyme . . . they load the concoction into their unimaginably super-tiny straws, which lets it be released v e r y slowly.

This works.  What the data shows is that this thermostablized enzyme eats up the neuron-hating CSPG over time . . . even after six weeks, they don’t come back.

The straws are formally called lipid microtubes, which can become part of a combination therapy.  Got that?  He’s discussing a piece — a necessary piece — to what will be a very intricate set of puzzle pieces.  The next step will be to collaborate with others who are working on the rest of the pieces.

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2 Comments on “Ravi Bellamkonda”

  1. mld Says:

    http://en.wikipedia.org/wiki/Trehalose

    “In nature, trehalose can be found in animals, plants, and microorganisms. In animals, trehalose is prevalent in shrimp, and also in insects, including grasshoppers, locusts, butterflies, and bees, in which blood-sugar is trehalose. The trehalose is then broken down into glucose by the catabolic enzyme trehalase for use. Trehalose is also present in the nutrition exchange liquid of hornets and their larvae.

    In plants, the presence of trehalose is seen in sunflower seeds, moonwort, Selaginella plants,[8] and sea algae. Within the fungi, it is prevalent in some mushrooms, such as shiitake (Lentinula edodes), maitake (Grifola fondosa), nameko (Pholiota nameko), and Judas’s ear (Auricularia auricula-judae), which can contain 1% to 17% percent of trehalose in dry weight form (thus it is also referred to as mushroom sugar). Trehalose can also be found in such microorganisms as baker’s yeast and wine yeast, and it is metabolized by a number of bacteria, including Streptococcus mutans, the common oral bacterium responsible for dental plaque.

    When tardigrades (water bears) dry out, the glucose in their bodies changes to trehalose when they enter a state called cryptobiosis — a state wherein they appear dead. However, when they receive water, they revive and return to their metabolic state. It is also thought that the reason the larvae of sleeping chironomid (Polypedilum vanderplanki) and artemia (sea monkeys, brine shrimp) are able to withstand dehydration is because they store trehalose within their cells.

    Even within the plant kingdom, Selaginella (sometimes called the resurrection plant), which grows in desert and mountainous areas, may be cracked and dried out, but will turn green again and revive after a rain because of the function of trehalose.[8] It is also said that the reason dried shiitake mushrooms spring back into shape so well in water is because they contain trehalose.

    The two prevalent theories as to how trehalose works within the organism in the state of cryptobiosis are the vitrification theory, a state that prevents ice formation, or the water displacement theory, whereby water is replaced by trehalose,[9] although it is possible that a combination of the two mechanisms is at work.

    The enzyme trehalase, a glycoside hydrolase, present but not abundant in most people, breaks trehalose into two glucose molecules, which can then be readily absorbed in the gut.

    Trehalose is the major carbohydrate energy storage molecule used by insects for flight. One possible reason for this is that the glycosidic linkage of trehalose, when acted upon by an insect trehalase, releases two molecules of glucose, which is required for the rapid energy requirements of flight. This is double the efficiency of glucose release from the storage polymer starch, for which cleavage of one glycosidic linkage releases only one glucose molecule.”


  2. […]  #6. Ravi Bellamkonda’s clever and necessary delivery system for ChABC, the 50-100 nanometer microtube that lets the ChABC go after the CSPGs for as long as six weeks with a single application. […]


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