Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-01-05
1998-05-12
Ulm, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
435 691, 530350, A61K 3816
Patent
active
057505020
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Throughout this application various references are referred to within parenthesis. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the sequence listing and the claims.
The early development of the vertebrate nervous system is controlled by local cell interactions that determine the identity of specific neural cell types and the pathways of growing axons. One of the first cell types to differentiate within the embryonic nervous system is the floor plate, a small group of epithelial cells located at the ventral midline of the neural tube (Schoenwolf and Smith, 1990). The differentiation of the floor plate is induced by local, possibly contact-dependent signals from the notochord (FIG. 1) (van Straaten et al., 1988; Placzek et al., 1990c; Hatta et al., 1991). Signals that derive from the floor plate have been implicated in the control of cell identity in the neural tube and in the guidance of axons (FIG. 1) (Jessell and Dodd, 1991).
Evidence that the floor plate is a source of polarizing signals that control cell identity and pattern in the neural tube has come from experiments in chick embryos in which floor plate cells grafted next to the neural tube of host embryos give rise to additional ectopic motor neurons and to other ventral neuronal types defined by cell specific antigenic markers (Yamada et al., 1991; Placzek et al., 1991). Inversely, preventing floor plate differentiation by removing the notochord leads to the formation of a spinal cord that is devoid of motor neurons and other ventral neurons. These grafting experiments suggest that the floor plate has a central role in establishing the identity and pattern of neuronal cell types present in the ventral spinal cord. The floor plate also has limb polarizing activity when grafted into the chick wing bud, possibly through the release of morphogenically active retinoids (Wagner et al., 1990).
After the identity of spinal cord neurons has been established, the floor plate appears to provide both long-range and local guidance cues that promote the growth of axons to and across the ventral midline of the spinal cord. First, the floor plate secretes a diffusible chemoattractant which can orient the growth of axons of commissural neuron in vitro (FIG. 1) (Tessier-Lavigne et al., 1988; Placzek et al., 1990a; Tessier-Lavigne and Placzek, 1991) and may account for the homing of these axons to the floor plate in vitro (Weber, 1938; Placzek et al., 1990b; Bovolenta and Dodd, 1991; Yaginuma and Oppenheim, 1991). Second, the floor plate may contribute to the change in trajectory of commissural axons from the transverse to the longitudinal plane that occurs immediately after crossing the ventral midline (FIG. 1) (Holley and Silver, 1987; Dodd et al., 1988; Bovolenta and Dodd, 1990). In support of this proposal, genetic mutations in mice and zebrafish that result in the absence of the floor plate during embryonic development lead to errors in the pathfinding of commissural axons at the midline of the spinal cord (Bovolenta and Dodd, 1991; Bernhardt and Kuwada, 1990).
Third, the floor plate may promote the fasciculation of commissural axons that occurs after they cross the midline of the spinal cord (Holley and Silver, 1987) by regulating the expression of glycoproteins of the immunoglobulin superfamily (Dodd et al., 1988; Schachner et al., 1990; Furley et al., 1990). The specialized role of the floor plate in vertebrate neural development has parallels in invertebrate organisms in that cells at the midline of the embryonic Diosophila and C. elegans central nervous systems have been implicated in neural patterning and axon guidance (Klambt et al., 1991; Nambu et al., 1991; Hedgecock and Hall, 1990).
To identify molecules that may mediate the diverse functions of the floor plate during early neur
REFERENCES:
Frazier, W.A., "Thrombospondin: a Molecular Adhesive Glycoprotein of Platelets and Nucleated Cells", J. Cell. Biol., vol. 105, Aug. 1987, pp. 625-632.
Henderson C.E., et al., "Neurite Outgrowth from Embryonic Chicken Spinal Neurons is Promoted by Media Conditioned by Muscle Cells", Proceedings of the National Academy of Sciences USA, vol. 78, No. 4, Apr. 1981, pp. 2625-2629.
Jacobson, M., "The Germinal Cell, Histogenesis, and Lineages of Nerve Cells", 1991 Developmental Neurobiology, (3rd Edition) Plenum Press--New York & London, pp. 41-93.
Jessell, T.M. and Dodd, J., "Floor Plate-Derived Signals and the Control of Neural Cell Pattern in Vertebrates", 1992, The Harvey Lectures, Series 86, pp. 87-128.
Jessell, T.M. and Dodd, J., "Cell Differentiation, Axon Guidance, and Target Recognition in Vertebrate Neural Development: A Brief Overview", (1991), Neurodegenerative Disorders: Mechanisms and Prospects for Therapy, pp. 105-126.
Klar A., et al., "F-Spondin: a Gene Expressed at High-Levels in the Floor Plate Encodes a Secreted Protein That Promotes Neural Cell Adhesion and Neurite Extension", Cell, vol. 69, Apr. 3, 1992, pp. 95-110.
Kosfeld M.D. et al., "Cell Attachment Activity of the Carboxy-Terminal Domain of Human Thrombospondin Expressed in Escherichia coli", J. Biol. Chem., vol. 266, No. 36, Dec. 25, 1991, pp. 24257-24259.
O'Shea K.S. et al., "Thrombospondin and a 140Kd Fragment Promote Adhesion and Neurite Outgrowth from Embryonic Central and Peripheral Neurons and from PC12 Cells", Neuron, vol. 7, Aug. 1991, pp. 231-237.
Osterhout D.J., et al., "Thrombospondin Promotes Process Outgrowth in Neurons from the Peripheral and Central Nervous Systems", Development Biology, vol. 150, 1992, pp. 256-265.
Placzek M. et al., "Mesodermal Control of Neural Cell Identity: Floor Plate Induction by the Notochord", Science, vol. 250, Nov. 16, 1990, pp. 985-988.
Sigma Catalog, 1989, p. 116.
Jessell Thomas M.
Klar Avihu
Brown Karen E.
The Trustees of Columbia University in City of New York
Ulm John
White John P.
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