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Pan-neurotrophin 1:...
Pan-neurotrophin 1: a genetically engineered neurotrophic factor displaying multiple specificities in peripheral neurons in vitro and in vivo
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ILAG, LL (author)
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CURTIS, R (author)
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GLASS, D (author)
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FUNAKOSHI, H (author)
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TOBKES, NJ (author)
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RYAN, TE (author)
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ACHESON, A (author)
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LINDSAY, RM (author)
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PERSSON, H (author)
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YANCOPOULOS, GD (author)
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DISTEFANO, PS (author)
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- IBANEZ, CF (author)
- Karolinska Institutet
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(creator_code:org_t)
- 1995-01-17
- 1995
- English.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 92:2, s. 607-611
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http://www.pnas.org/...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
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- Pan-neurotrophin 1 (PNT-1) is a synthetic trophic factor engineered by combining active domains of the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3) into an NT-3 backbone. This molecule was produced in transiently transfected COS cells or in baculovirus-infected insect cells transfected COS cells or in baculovirus-infected insect cells and subsequently purified to homogeneity. Saturation binding in embryonic spinal sensory neurons demonstrated a greater number of high-affinity binding sites for PNT-1 than for its parental molecule NT-3. PNT-1 was shown to efficiently block the chemical crosslinking of NGF, BDNF, and NT-3 to their cognate Trk receptors and to the low-affintiy NGF receptor expressed on neuronal and nonneuronal cells. PNT-1 stimulated survival and proliferation of MG87 fibroblasts expressing either TrkA, TrkB, or TrkC. PNT-1 also promoted survival of a greater number of embryonic dorsal root ganglion neurons than any of the other neurotrophins alone, and its effects were equivalent to a combination of NGF, BDNF, and NT-3. Analysis of receptor-specific neurotrophic activities demonstrated that PNT-1 efficiently rescued TrkA mRNA-containing sympathetic neurons and TrkB and TrkC mRNA-containing sensory neurons from the dorsal root and nodose ganglia. Finally, PNT-1 showed robust retrograde transport to DRG neurons in vivo after injection into the sciatic nerve. Radiolabeled PNT-1 accumulated in small-, medium-, and large-sized neurons. Coinjection with different unlabeled neurotrophins inhibited PNT-1 transport in distinct subpopulations of neurons of different sizes, suggesting that this molecule affects sensory neurons of different modalities. These results indicate that PNT-1 is a potent and multispecific neurotrophic factor that may be useful in the treatment of peripheral neurophathies and nerve damage.
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ILAG, LL
-
CURTIS, R
-
GLASS, D
-
FUNAKOSHI, H
-
TOBKES, NJ
-
RYAN, TE
-
show more...
-
ACHESON, A
-
LINDSAY, RM
-
PERSSON, H
-
YANCOPOULOS, GD
-
DISTEFANO, PS
-
IBANEZ, CF
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show less...
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Karolinska Institutet