| Methods for modulating neuronal responses -> Monitor Keywords |
|
|
 
Methods for modulating neuronal responsesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) DoaiMethods for modulating neuronal responses description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060234912, Methods for modulating neuronal responses. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The invention is, in general, in the field of neurology. More specifically, the invention provides, in part, methods and reagents for modulating neuronal apoptosis or synaptic plasticity. BACKGROUND OF THE INVENTION [0002] Synaptic transmission is the process by which neurons communicate by excitatory (generation of an action potential) or inhibitory (inhibition of an action potential following excitation) mechanisms. Excitatory synaptic transmission often occurs by means of the neurotransmitter L-glutamate and its cognate glutamate receptors, which include the N-methyl-D-aspartate (NMDA) and .alpha.-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype glutamate receptors. Synaptic plasticity refers to the use-dependent ability of post-synaptic neurons to modulate their response to the release of neurotransmitters during synaptic transmission, and is thought to be important in learning and memory processes. [0003] The excessive stimulation of post-synaptic neurons (a phenomenon known as "excitotoxicity"), which can lead to neuronal death or apoptosis, has been implicated in a variety of central nervous system (CNS) disorders. Activation of the NMDA receptor may induce programmed cell death (apoptosis) in cultured hippocampal neurons, and may underlie the loss of neurons and neuronal function in central nervous system disorders ranging from acute brain trauma and stroke to neurogenerative diseases such as Huntington's, Alzheimer's, and Parkinson's Diseases..sup.1-5 [0004] NMDA receptor activation may also lead to facilitation of clathrin-mediated endocytosis of AMPA receptors, which mediate fast synaptic transmission at excitatory synapses in the mammalian CNS..sup.6,7 AMPA receptor function can be modified at the level of open channel probability.sup.34, channel conductance.sup.27;33, and the kinetics of desensitization..sup.52 Rapid redistribution of AMPA receptors to and from the postsynaptic domain is also thought to be a means of regulating the strength of AMPA receptor-mediated synaptic transmission..sup.43;45;6 AMPA receptors undergo functionally distinct constitutive and regulated clathrin-dependent cycling between intracellular compartments and the plasma membrane via vesicle-mediated plasma membrane insertion (exocytosis) and internalization (endocytosis)..sup.22;30;20;24;41;14 Regulating these processes can lead to rapid changes in the number of AMPA receptors expressed in the postsynaptic membrane, thereby contributing to the expression of certain forms of synaptic plasticity, including hippocampal long term potentiation (LTP) .sup.35;42;50 and long term depression (LTD) in the cerebellum and hippocampus..sup.14;24;25;44 AMPA receptors may be subjected to stimulated endocytosis by diverse stimuli including growth factors, such as insulin/IGF-1 .sup.14;25, agonist binding.sup.22;21;20, and LTD-producing protocols..sup.24;14;25 SUMMARY OF THE INVENTION [0005] The invention provides, in part, methods and reagents for modulating neuronal apoptosis. The invention also provides, in part, methods and reagents for modulating synaptic plasticity. [0006] In some aspects, the invention provides a method of modulating NMDA-mediated neuronal apoptosis by contacting a neuronal cell with an inhibitor of AMPA receptor endocytosis. In alternative aspects, the invention provides a method of modulating NMDA-mediated neuronal apoptosis by contacting a neuronal cell with an inhibitor of clathrin-mediated endocytosis. In alternative aspects, the invention provides a method of treating or preventing neurological damage or dysfunction in a subject by administering an effective amount of an inhibitor of AMPA receptor endocytosis to the subject. [0007] In alternative embodiments, the neurological damage may include NMDA-induced neuronal apoptosis, or may occur as a result of excessive activation of NMDA receptors or due to changes in AMPA receptor endocytosis, or may occur as a result of at least one of a disorder selected from the group consisting of stress, anxiety, depression, hypoglycemia, cardiac arrest, epilepsy, cerebral ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's disease; neuropathic pain; amyotrophic lateral sclerosis (ALS); Hutchinson Gilford syndrome; diabetes; ataxia; mental retardation; dementias, disorders associated with smoking or obesity, high blood pressure, disorders associated with defects or dysfunction in learning or memory, psychiatric disorders, autism, schizophrenia, fragile X syndrome, or disorders associated with substance abuse or addiction to a drug (e.g., nicotine, alcohol, opiates, heroin, codeine, morphine pethidine, methadone, marijuana, phenyclidene, psychostimulants, amphetamines, cocaine, barbiturates, pentobarbitone, quinalbarbitone, benzodiazepines, temazepam, diazepam or flunitrazepam). [0008] In alternative aspects, the invention provides a method of modulating synaptic plasticity in a subject by administering an effective amount of an inhibitor of AMPA receptor endocytosis to the subject (e.g., a normal subject i.e. one not having or not diagnosed with neurological damage or dysfunction). In alternative embodiments, the method may further include enhancing synaptic plasticity. In alternative acts, the invention provides a method of treating or preventing substance abuse in a subject by administering an effective amount of an inhibitor of AMPA receptor endocytosis to the subject. [0009] In some aspects, the invention provides a method of modulating AMPA receptor endocytosis by contacting a cell or system (for example, a lipid vehicle) expressing an AMPA receptor with a peptide comprising an amino acid sequence selected from the group consisting of YREGYNVYGIE, YKEGYNVYGIE, YREGYNVYG, or YKEGYNVYG, or with an antibody that specifically binds an amino acid sequence selected from the group consisting of YREGYNVYGIE, YKEGYNVYGIE, YREGYNVYG, and YKEGYNVYG. [0010] In some aspects, the invention provides a method of modulating AMPA receptor endocytosis, by contacting a cell expressing an AMPA receptor with a modulatory compound comprising the amino acid sequence set forth in Table I or conservative substitutions thereof. Formula I, or Formula A, or homologous sequences thereto found in the C-terminus of the GluR2, GluR3, or GluR4 subunits of the AMPA receptor or a fragment or variant thereof, or comprising an antibody that specifically binds the amino acid sequence set forth in Table I or conservative substitutions thereof, Formula I, or Formula A, or homologous sequences thereto found in the C-terminus of the GluR2, GluR3, or GluR4 subunits of the AMPA receptor. [0011] In alternative aspects, the invention provides a method of screening for a modulator of AMPA receptor endocytosis, by providing a system including an AMPA receptor polypeptide or a biologically-active fragment thereof; an inhibitor of AMPA receptor endocytosis; providing a test compound; contacting the system with the test compound; and deter whether the test compound modulates AMPA receptor endocytosis. [0012] In alternative aspects, the invention provides a method of screening for a modulator of AMPA receptor endocytosis, the method including providing an AMPA receptor polypeptide or a biologically-active fragment thereof; providing an inhibitor of AMPA receptor endocytosis; providing a test compound; contacting the AMPA receptor polypeptide or a biologically-active fragment thereof with the test compound or the inhibitor; and determining whether the test compound modulates AMPA receptor endocytosis [0013] In alternative aspects, the invention provides a method of screening for a modulator of AMPA receptor endocytosis, by providing an AMPA receptor polypeptide or a biologically-active fragment thereof; providing a test compound; contacting the AMPA receptor polypeptide or a biologically-active fragment thereof with the test compound; and determining whether the test compound modulates AMPA receptor endocytosis. In alternative embodiments, the method may further include providing an inhibitor of AMPA receptor endocytosis, contacting the AMPA receptor polypeptide or a biologically-active fragment thereof with the inhibitor, and determining whether the test compound modulates AMPA receptor endocytosis when compared to the inhibitor. [0014] In alternative aspects, the invention provides a polypeptide including an amino acid sequence substantially identical to the sequence of YREGYNVYGIE, YKEGYNVYGIE, YREGYNVYG, or YKEGYNVYG, or a nucleic acid molecule encoding any of these amino acid sequences, or an antibody that specifically binds any of these amino acid sequences. [0015] In alternative aspects, the invention provides a substantially pure compound including Formula I: Z.sub.1-X.sub.1-X.sub.2-E-G-X.sub.3-N-V-X.sub.4-G-Z.sub.2; where X.sub.1 may be Y, D, E, S, or T; X.sub.2 may be K or R; X.sub.3 is Y, D, E, S, or T; X.sub.4 may be Y, D, E, S, or T; Z.sub.1 may be H.sub.2N--, RHN-- or, RRN--; Z.sub.2 may be --C(O)OH, --C(O)R, --C(O)OR, --C(O)NHR, --C(O)NRR; R at each occurrence may be independently selected from (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkenyl, (C.sub.1-C.sub.6) alkynyl, substituted (C.sub.1-C.sub.6) alkyl, substituted (C.sub.1-C.sub.6) alkenyl, or substituted (C.sub.1-C.sub.6) alkynyl; wherein "--" may be a covalent linkage, and wherein the compound may be an inhibitor of AMPA a endocytosis. In alternative embodiments, any one or more of X.sub.1, X.sub.3, or X maybe a Y. [0016] In alternative aspects, the invention provides a substantially pure compound including Formula A: Z.sub.1-X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-X.sub.8-X- .sub.9-Z.sub.2, where X.sub.1 may be an amino acid having a hydropathic index of -0.3 to 4.3 or of -1.3 to -3.3 or may be a neutral or an acidic amino acid, or may Gly, Ser, Thr, Cys, Asn, Gln, Tyr, Asp, Glu; X.sub.2 may be an amino acid having a hydropathic index of +1.0 to +5.0 or of +2.0 to +4.0 or may be a basic amino acid or may be Lys, Arg, His; X.sub.3 may be an amino acid having a hydropathic index of +1.0 to +5.0 or of +2.0 to +4.0 or may be an acidic amino acid or may be Asp, Glu; X.sub.4 may be an amino acid having a hydropathic index of -2.0 to +2.0 or of -1.0 to +1.0 to or may be a neutral amino acid or may be Gly, Ser, Thr, Cys, Asn, Gln, Tyr, X.sub.5 may be an amino acid having a hydropathic index of 0.3 to 4.3 or of -1.3 to -3.3 or may be a neutral or an acidic amino acid or may be Gly, Ser, Thr, Cys, Asn, Gln, Tyr, Asp, Glu; X.sub.6 may be an amino acid having a hydropathic index of-1.8 to +2.2 or of -0.8 to +1.2 or may be a neutral amino acid or may be Gly, Ser, Thy, Cys, Asn, Gln, Tyr; X.sub.7 may be an amino acid having a hydropathic index of -3.5 to 0.5 or of -2.5 to -0.5 or nay be a non-polar amino acid or may be Ala, Val, Leu, Ile, Phe, Trp, Pro, Met; X8 may be an amino acid having a hydropathic index of -0.3 to -4.3 or of -1.3 to -3.3 or may be a neutral or an acidic amino acid or may be Gly, Ser, 1 hr, Cys, Asn, Gin, Tyr, Asp, Glu; X.sub.9 may be an amino acid having a hydropathic index of -2.0 to +2.0 or of -1.0 to +1.0 to may be a neutral amino acid or may be Gly, Ser, Thr, Cys, Asn, Gln, Tyr, Z, is H.sub.2N--, RHN-- or, RRN--; Z.sub.2 may be C(O)OH, C(O)R, --C(O)OR, --C(O)NHR, --C(O)NRR; R at each occurrence may be independently selected from (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkenyl, (C.sub.1-C.sub.6) alkynyl, substituted (C.sub.1-C.sub.6) alkyl, substituted (C.sub.1-C.sub.6) alkenyl, or substituted (C.sub.1-C.sub.6) alkynyl; wherein "--" is a covalent linkage, and wherein the compound may be an inhibitor of AMPA receptor endocytosis. In alternative embodiments, any one or more of X.sub.1, X.sub.5, or X.sub.8 may be a Y. [0017] In alternative embodiments, the compound of Formula I or A may inhibit AMPA receptor endocytosis with an affinity that is at least as great as the affinity when the compound is a polypeptide including a sequence of YREGYNVYGIE, YKEGYNVYGIE, YREGYNVYG, or YKEGYNVYG. In alternative embodiments, the compound of Formula I or A may include a similarity score of over zero based on either of the PAM or Blosum similarity matrices. In alternative embodiments, the compound of Formula I or A may further include the amino acid sequence YGRKKRRQRRR. [0018] In alternative aspects, the invention provides the use of any of the polypeptides, nucleic acid molecules, antibodies, or compounds according to the invention for treating or preventing neurological damage or substance abuse in a subject, or for modulating NMDA-mediated-neuronal apoptosis, or for modulating AMPA receptor endocytosis, or for modulating sync plasticity in a subject. [0019] In various embodiments of the aspects of the invention, the inhibitor may include an inhibitor of regulated AMPA receptor endocytosis. In various embodiments of the aspects of the invention, the inhibitor may include a GluR2, GluR3, or GluR4 polypeptide. In various embodiments of the aspects of the invention, the inhibitor of AMPA receptor endocytosis may include a peptide including any of the amino acid sequences of YREGYNVYGIE, YKEGYNVYGIE, YREGYNVYG, or YKEGYNVYG or a fragment or variant thereof, or may be a GluR2, GluR3, or GluR4 polypeptide, or may include an antibody that specifically binds any of the amino acid sequences of YREGYNVYGIE, YKEGYNVYGIE, YREGYNVYG, and YKEGYNVYG. In various embodiments of the aspects of the invention, the inhibitor may include the amino acid sequence set forth in Table I or conservative substitutions thereof, Formula I, or Formula A, or homologous sequences thereto found in the C-terminus of the GluR2, GluR3, or GluR4 subunits of the AMPA receptor or a fragment or variant thereof or include an antibody that specifically binds the amino acid sequence set forth in Table I or conservative substitutions thereof, Formula L or Formula A, or homologous sequences thereto found in the C-terminus of the GluR2, GluR3, or GluR4 subunits of the AMPA receptor. In various embodiments of the aspects of the invention, may further include the amino acid sequence YGRKKRRQRRR. [0020] .alpha.-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or "AMPA" receptors are glutamate-gated ion channel receptors that are involved in transduction of the post-synaptic signal. Native AMPA receptors may be heteromeric, e.g, heteropentameric, protein complexes assembled from combinations of GluR subunits 1-4. When transiently expressed in non-neuronal mammalian cells, individual GluR subunits can form functional homomeric AMPA receptor channels, and AMPA receptors in these heterologous expression systems can undergo both constitutive and regulated clathrin-dependent endocytosis. In some embodiments, an AMPA receptor includes a GluR2 subunit. GluR subunits may include without limitation the sequences described in Accession numbers NP.sub.--113796; NPL032191; NP.sub.--000818 for GluR1; NP_058957; NP.sub.--038568; NP.sub.--000817; P23819 for GluR2; NP.sub.--116785 for GluR3; or NP.sub.--058959 or NP.sub.--000820 for GluR4, and related nucleotide sequences, for example, NM.sub.--000826. Other GluR polypeptide or nucleotide sequences may be found in public databases, such as GenBank. [0021] A "phosphorylated" AMPA receptor includes polypeptide subunits that are post-translationally modified on any amino acid residue, for example, serine, threonine, or tyrosine, that is capable of being phosphorylated in vivo. For example, a phosphorylated AMPA receptor may include a GluR2 subunit that is phosphorylated, for example, on any one or more of tyrosines 869, 873, and 876 of the sequence described in Accession number NP.sub.--000817, or phosphorylated on any one or more of tyrosine residues present in corresponding sequences in GluR subunits. Continue reading about Methods for modulating neuronal responses... Full patent description for Methods for modulating neuronal responses Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods for modulating neuronal responses patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Methods for modulating neuronal responses or other areas of interest. ### Previous Patent Application: Methods for improving the structure and function of arterioles Next Patent Application: Methods for the treatment of insulin resistance and disease states characterized by insulin resistance Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Methods for modulating neuronal responses patent info. IP-related news and info Results in 0.1492 seconds Other interesting Feshpatents.com categories: Qualcomm , Schering-Plough , Schlumberger , Seagate , Siemens , Texas Instruments , 174 |
 * Protect your Inventions * US Patent Office filing 
PATENT INFO |
|
