Source: NYU Langone Medical Center / New York University School of Medicine
Date: 1 March 2009
New potential therapeutic target discovered for genetic disorder -- Barth syndrome
Researchers at NYU Langone Medical Center may have discovered a new targeted intervention for Barth Syndrome (BTHS). BTHS, a sometimes fatal disease, is a serious genetic disorder occurring predominantly in males that leads to infection or heart failure in childhood. The new study entitled, "Role of calcium-independent phospholipase A2 in the pathogenesis of Barth syndrome", was recently published in the Proceedings of the National Academy of Sciences, shows the benefits of targeted intervention with an iPLA2-VIA inhibitor that prevents a major symptom of the disease- cardiolipin deficiency.
"Our research has established a causal role of cardiolipin deficiency in the pathogenesis of Barth syndrome and identified an important enzyme in cardiolipin degradation called iPLA2-VIA as a potential target for therapeutic intervention of the disease," said Mindong Ren, Ph.D., lead investigator of the study and assistant professor of cell biology at NYU Langone Medical Center.
BTHS syndrome is an X-linked genetic cardioskeletal muscle disease resulting in muscle weakness and fatigue in patients. The debilitating disorder is caused by a mutation in the genetic coding of tafazzin, an enzyme of the cardiolipin pathway. Cardiolipin is an essential lipid in the inner membrane of mitochondria responsible for normal cell structure and energy production. BTHS patients exhibit defects in cardiolipin metabolism which help fight infections. The various symptoms of BTHS, in addition to cardiolipin deficiency, include cardiomyopathy (weakness in heart muscle), neutropenia (a reduction in neutrophils or white blood cells that fight bacterial infections), muscle weakness & fatigue (caused by cellular deficiency), growth delay, and increase of organic acids in urine.
In a previous study, NYU researchers documented the characteristics of a tafazzin-deficiency in a Drosophila (fruit fly) model of the disease, showing low and abnormal cardiolipin concentration, abnormal mitochondria, and poor motor function. In this new study researchers documented that tafazzin or cardiolipin deficiency in Drosophila disrupts the final stage of spermatogenesis causing male sterility. Using this fly model, the study showed that this trait of cardiolipin deficiency can be genetically suppressed by inactivating calcium-independent phospholipase A2, which prevents the degradation of cardiolipin. This method keeps cardiolipin levels normal. Researchers were also able to show that treatment of BTHS patients lymphoblasts within a tissue culture with the iPLA2-VIA inhibitor BEL partially restored the tissue cultures cardiolipin homeostasis.
"Taken together, our two findings establish a causal role of cardiolipin deficiency in the pathogenesis of Barth syndrome and identify iPLA2-VIA as a very important enzyme," said Michael Schlame, M.D., associate professor of anesthesiology and cell biology, NYU Langone Medical Center. "This is good news for patients since this enzyme is now a potential target for therapeutic intervention."
According to researchers, although this has not been tested in humans, the successful restoration of these mutated cells with BEL shows promise for continued BTHS research, patients and their families. There are no treatments for Barth syndrome at this time.
“You wait till Larry comes and I tell him my theory!” The bids, duly sealed, were given into the keeping of the commissary officer to be put in his safe, and kept until the day of judgment, when all being opened in public and in the presence of the aspirants, the lowest would[Pg 188] get the contract. It was a simple plan, and gave no more opportunity for underhand work than could be avoided. But there were opportunities for all that. It was barely possible—the thing had been done—for a commissary clerk or sergeant, desirous of adding to his pittance of pay, or of favoring a friend among the bidders, to tamper with the bids. By the same token there was no real reason why the commissary officer could not do it himself. Landor had never heard, or known, of such a case, but undoubtedly the way was there. It was a question of having the will and the possession of the safe keys. "Well, I believe our boys 's all right. They're green, and they're friskier than colts in a clover field, but they're all good stuff, and I believe we kin stand off any ordinary gang o' guerrillas. I'll chance it, anyhow. This's a mighty valuable train to risk, but it ought to go through, for we don't know how badly they may need it. You tell your engineer to go ahead carefully and give two long whistles if he sees anything dangerous." "Fine-looking lot of youngsters," he remarked. "They'll make good soldiers." "That's just what he was, the little runt, and we had the devil's own time finding him. What in Sam Hill did the Captain take him for, I'd like to know? Co. Q aint no nursery. Well, the bugler up at Brigade Headquarters blowed some sort of a call, and Skidmore wanted to know what it meant. They told him that it was an order for the youngest man in each company to come up there and get some milk for his coffee tomorrow morning, and butter for his bread. There was only enough issued for the youngest boys, and if he wanted his share he'd have to get a big hustle on him, for the feller whose nose he'd put out o' joint 'd try hard to get there ahead o' him, and get his share. So Skidmore went off at a dead run toward the sound of the bugle, with the boys looking after him and snickering. But he didn't come back at roll-call, nor at tattoo, and the smart Alecks begun to get scared, and abuse each other for setting up a job on a poor, innocent little boy. Osc Brewster and Ol Perry, who had been foremost in the trick had a fight as to which had been to blame. Taps come, and he didn't get back, and then we all became scared. I'd sent Jim Hunter over to Brigade Headquarters to look for him, but he came back, and said they hadn't seen anything of him there. Then I turned out the whole company to look for him. Of course, them too-awfully smart galoots of Co. A had to get very funny over our trouble. 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They made their way to him, and there was little Skidmore sitting on a stump, completely confused and fagged out. He'd lost his way, and the more he tried to find it the worse he got turned around. They called out to him, and he blubbered out: 'Yes, it's me; little Pete Skidmore. Them doddurned fools in my company 've lost me, just as I've bin tellin' 'em right along they would, durn 'em.' Osc and Ol were so tickled at finding him that they gathered him up, and come whooping back to camp, carrying him every step of the way." And the rush stopped. Cadnan waited for a second, but there was no more. "Dara is not to die," he said. Then he saw Orion hanging over him, very low in the windy sky, shaking with frost. His eyes fixed themselves on the constellation, then gradually he became aware of the sides of a cart, of the smell of straw, of the movement of other bodies that sighed and stirred beside him. The physical experience was now complete, and soon the emotional had shaped itself. Memory came, rather sick. He remembered the fight, his terror, the flaming straw, the crowd that constricted and crushed him like a snake. His rage and hate rekindled, but this time without focus—he hated just everyone and everything. He hated the wheels which jolted him, his body because it was bruised, the other bodies round him, the stars that danced above him, those unknown footsteps that tramped beside him on the road. Farewell to Jane and Caroline!" HoME大香蕉色人阁
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