| Methods for shp1 mediated neuroprotection -> Monitor Keywords |
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  Methods for shp1 mediated neuroprotectionRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Antigen-antibody Binding, Specific Binding Protein Assay Or Specific Ligand-receptor Binding Assay, Involving A Micro-organism Or Cell Membrane Bound Antigen Or Cell Membrane Bound Receptor Or Cell Membrane Bound Antibody Or Microbial LysateThe Patent Description & Claims data below is from USPTO Patent Application 20070009967. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a divisional application and claims priority from U.S. application Ser. No. 10/386,243, filed Mar. 11, 2003. The complete disclosure of the aforementioned U.S. patent application is hereby incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention provides methods to use SHP1 modulators for neuroprotection and assays capable of identifying SHP1 modulators. BACKGROUND OF THE INVENTION [0003] This patent application claims priority from U.S. Provisional patent application No. 60/363,440 filed Mar. 11, 2002 and entitled "Methods and Compositions for SHP1 mediated Neuroprotection." [0004] Erythropoietin (EPO) is responsible for the maintenance, increase and terminal differentiation of erythroid progenitor cells. Erythropoiesis is controlled by the production of erythropoictin in the kidney as a function of oxygen tension in the blood. Recent data has shown that other cell types, including endothelial cells [26], kidney cells [33] and neuronal cells [22], also contain functional EPO receptor (EPOR). [0005] Several lines of evidence support the function of EPO as a neuroprotective molecule. First, both EPO and its receptor have been found in neural tissues [11], including rat hippocampal neurons and subsets of neurons in the rat cerebral cortex [21]. Second, in a series of in vitro experiments, EPO has been shown to prevent the death of neurons in response to a variety of insults including glutamate toxicity and hypoxia [21, 28]. In addition, the neuroprotective effects of EPO have been demonstrated in several in vivo models of CNS injury. Intraventricular administration of EPO significantly decreased the damage observed in an ischemic gerbil model [27], and in a mouse model of middle cerebral a occlusion [3]. Recently, reports have shown that EPO administered systemically can cross the blood brain barrier and have a protective effect in in vivo models of stroke blunt trauma [5] and su arachnoid hemorrhage-induced acute cerebral ischemia [1]. In addition, EPO has been suggested to be the factor responsible for the increased survival, differentiation and proliferation of neuronal stem cells that are cultured under conditions of low oxygen [30]. These result suggest that EPO can be useful as a neuroprotective molecule for the treatment of nervous system conditions, such as stroke, and other neurodegenerative diseases. [0006] U.S. Pat. No. 6,165,783 states that "[t]he erythropoietin may be exogenously applied to the multipotent neural stem cells, or alternatively, the cells can be subjected to hypoxic insult which induces the cells to express erythropoietin." [0007] EPO exerts its biological effect by binding to preexisting receptor dimers located on the cell and inducing a conformational change in the EPO receptor, EPOR. The change in EPOR conformation results in the activation of JAK2 and the subsequent phosphorylation of tyrosine residues on the EPO receptor and other intracellular proteins such as ERKs, She and Stat5 [6, 4]. The change in EPOR conformation also results in recruitments of SH2 domain containing proteins to the receptor complex, including the SH2 containing protein tyrosine phosphatase (PTPase) SHP1, also known as SH-PTP1, PTP1C, HCP or SHP, which dephosphorylates JAK2 and subsequently inactivates JAK2. Due to the presence of high levels of SHP1 in all hematopoietic cell lineages at all stages of hematopoietic cell differentiation, phosphorylation of EPO is transient with the loss of detectable phosphorylation on tyrosine residue(s) of EPOR within thin minutes after the initial binding of EPO to EPOR. While the function of EPO to protect neurons from cell death is consistent with the function of EPO in hematopoietic cells, the potency of the effect of EPO on neuronal cells increased significantly as compared with hematopoietic cells. EPO has been observed to be effective at pM concentrations in neurons while nM levels of EPO are required to elicit the same effects in hematopoietic cells [27, 13]. [0008] The mechanism for increased potency of EPO in neuronal cells is not clear. Previous reports have indicate, that the EPOR expressed in neurons is identical in sequence to that found in hematopoietic cells, including all potential sites of tyrosine phosphorylation, and that EPOR expressed in neurons has a lower affinity for EPO [18]. While the possibility exists that the EPOR is different in neurons due to variations in post-translational modifications, the relative low affinity of EPO for the EPOR in neurons and the observation that EPO activates similar signaling pathways to neuronal cells similar to those in hematopoietic cells make it unlikely that changes in EPOR alone accounts for the increased potency of EPO in neuronal cells. [0009] Little is known about the role of SHP1 in EPOR activated signal transduction pathway in cells of the nervous system in part because there is little information concerning the expression or function of SHP1 in CNS. SHP1 has been reported to be present in specific neuron subtypes [10] and to negatively regulate specific functions in rob cell lines [20]. Stimulation of neutrophils with chemotactic peptides is known to result in the activation of tyrosine kinases that mediate neutrophil responses (Cui et al., J. Immunol., 1994) and the PTPase activity of SHP1 modulates agonist-induced activity by reversing the effects of tyrosine kinases activated in the initial phases of cell stimulation U.S. Pat. No. 6,261,279 suggests that "agents that could stimulate PTPase activity could have potential therapeutic applications as anti-inflammatory mediators." Although it has been reported that SHP1 can act as a positive signal in RAS-mediated activation of the mitogen-activated protein kinase pathway, it is not known what regulatory role SHP1 plays in EPOR activated signal transduction pathway in cells of the nervous system. [0010] Understanding the role of SHP1 in EPOR activated signal transduction pathway in cells of the nervous system can shed light on the mechanism of the neuroprotection function of EPO, which in turn can help the design and identification of novel neuroprotective molecules. SUMMARY OF INVENTION [0011] It has now been discovered that treating cells of the nervous system with EPO results in decreased expression of SHP1 in the cell. This down regulation of SHP1 then prevents the timely dephosphorylation of the EPOR thus allowing for a sustained activation of both the EPOR itself and downstream targets such as ERK1/ERK2. The sustained activation of EPOR can explain the high potency of EPO in the cells of nervous system. [0012] In one general aspect, the invention therefore provides a method for treating a nervous system condition related to EPOR in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective dose of a composition that decrease the tyrosine phosphatase activity of a SHP1 in a cell of the nerve system of the subject. For example, the subject can be in need of treatment for neuroprotection. [0013] In other general aspects, the invention provides a method for tang a nervous system on related to EPOR in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective dose of a composition that decreases the expression of a SHP1 in a cell of the nerve system of the subject. For example, the composition comprises an antisense nucleic acid or a siRNA molecule specific for an SHP1 gene and the antisense nucleic acid or siRNA molecule specifically suppresses SHP1 gene expression. [0014] An additional general aspect of the invention is a method of identifying a compound useful for treating a nervous system condition related to EPOR, comprising the steps of: [0015] 1) contacting a test compound with an SHP1 protein or an active fragment thereof; and [0016] 2) determining the ability of the test compound to decease the tyrosine phosphatase activity of SHP1. [0017] Further general aspect of the invention is a method of identifying a compound useful for treating a nervous system condition related to EPOR, comprising the steps of: [0018] a) contacting a test compound with a regulatory sequence for a SHP1 gene or a cellular component that binds to the regulatory sequence for a SHP1 gene; and [0019] b) determining whether the test compound decreases the expression of a gene controlled by said regulatory sequence. [0020] Yet another general aspect of the invention is a method of identifying a compound useful for treating a nervous system condition related to EPOR, comprising the steps of: [0021] a) combining a test compound, a labeled ligand for a SHP1 protein, and a SHP1 protein or an active fragment thereof; and [0022] b) measuring the binding of the test compound to the SHP1 protein or active fragment thereof by a reduction in the amount of labeled ligand binding to the SHP1 protein or active fragment thereof. [0023] In preferred embodiments of the invention, the methods of identifying a compound useful for treating a nervous system condition related to EPOR, further comprise the steps of [0024] a) contacting a neuronal cell with the test compound; [0025] b) inducing neurotoxicity in the neuronal cell; [0026] c) assaying the cell survival rate in the presence of the test compound, [0027] and comparing the cell survival rate with that of a control wherein the neuronal cell is not treated with the test compound. [0028] Other aspects, features and advantages of the invention will be apparent from the following disclosure, including the detailed description of the invention and its preferred embodiment and the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS Continue reading... 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