神经营养因子与神经生长和修复.ppt
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1、1,Neurotrophic factors and Their receptors,Huang Shu-Hong Institute of neurobiology,2,For decades, scientists believed that brain cells of the central nervous system could not regrow following damage due to trauma such as head injury or disorders such as Alzheimers disease. Treatments did not exist.
2、 The outlook was bleak.,3,But now that thinking has been turned upside down. Scientists recently have discovered a whole family of proteins called neurotrophic factors. These proteins play a crucial role in the development and survival of nerve cells, or neurons, and in supporting adult neurons to k
3、eep them healthy throughout life.,4,1934: Victor Hamburger discovered that removal of a limb bud resulted in reduced numbers of sensory and motor neurons in the spinal cord.,The neurotrophic factor hypothesis,5,Effect of Removing or Augmenting Neural Targets on the Survival of Related Neurons,PN2309
4、2.JPG,1939: Victor Hamburger showed that transplantation of a supernumerary limb resulted in increased numbers of sensory and motor neurons in the spinal cord.,6,Based on his limb-bud experiments, V. Hamburger hypothesized that the targets of innervating neurons provide signals that recruit undiffer
5、entiated cells to develop into sensory or motor neurons.,(he was wrong),In 1942, Levi-Montalcini and Levi proposed that target derived signals maintain survival of differentiating neurons. In 1949, Hamburger and Levi-Montalcini repeated the limb bud experiments and found that their results supported
6、 the neurotrophic hypothesis. Hamburger, V. and Levi-Montalcini, R. (1949) J. Exp. Zool. 111: 457-502.,The neurotrophic factor hypothesis,7,8,1954: neurite outgrowth assay, extract,+ extract,1969: NGF purified to homogeneity,Stanley Cohen,Rita Levi-Montalcini,1986: Levi-Montalcini and Cohen split th
7、e Nobel prize for Physiology or Medicine “for their discovery of growth factors”,1960: NGF purified,9,NGF: sympathetic neurons and some sensory neurons,(CNS neurons do not require NGF for survival),BDNF: NGF-related factor purified in 1982 from pig brain (shares 50% homolog with NGF),NT-3 and NT-4/5
8、: were obtained by PCR cloning,All these factors are synthesized as 250 aa precursors that are processed into 120 aa proteins,The main List of Neurotrophic Factors,10,Neurotrophins BDNF (brain derived neurotrophic factor) on cortical neurons,11,12,13,14,Trk receptor signaling,When a neurotrophin bin
9、ds to a trk receptor, the kinase domain is activated resulting in autophosphorylation.,Autophoshorylation results in further activation of the kinase domain, leading to activation of three potential signaling cascades:,MAPK,PI3K,PLC-g,15,16,Other neurotrophic Factors,17,18,Structure of neurotrophic
10、Factor receptors,19,Alternative splicing generates many Trk receptor isoforms,Roux and Barker (2002) Prog Neurobiol 67:203-233,NGF KD for TrkA=10-11M,20,p75NTR structure,NGF KD=10-9M (all neurotrophins can bind p75NTR),Roux and Barker (2002) Prog Neurobiol 67:203-233,21,Models for Trk and p75NTR int
11、eraction,Chao and Bothwell (2002) Neuron 33:9-12,22,The effect of NT/NTR knockouts on neurons in the DRG,Farias et al. (2002) Brain Res Bull 57:809-816,23,Our axons can be 1 m in length-how does the neurotrophin/receptor complex signal to the neuronal cell body?,Miller and Kaplan (2001) Neuron 32:76
12、7-770,24,Campenot, RB (1977) Local control of neurite development by nerve growth factor. Proc Natl Acad Sci U S A. 74(10):4516-9.,(A method that can be used to study how NTs added to distal axons signal retrogradely),Miller and Kaplan (2001) Neuron 32:767-770,NGF,+K252a,25,26,Activated Trk can sign
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- 神经 营养 因子 生长 修复
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