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Compositions and Methods for Treating and Preventing Pancreatitis, Renal Injury and Cancer

a technology of renal injury and compositions, applied in the field of compositions and methods for treating and preventing pancreatitis, renal injury and cancer, can solve the problems of increasing morbidity and mortality, worsening severity, and increasing the activity of ckd, so as to reduce the the level of activity of a renalase receptor

Inactive Publication Date: 2017-04-20
YALE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method of treating or preventing kidney and pancreatic diseases or disorders in humans by administering a therapeutically effective amount of a composition containing a renalase polypeptide or a fragment or conjugate thereof. The renalase polypeptide can be a recombinant protein or a peptidomemetic, and can be administered alone or in combination with other agents such as a PMCA4b activator. The method can involve administering the composition one time or repeatedly, and can involve local, regional, or systemic administration. The patent also describes a method of treating or preventing cancer by administering a composition containing a PMCA4b inhibitor. Overall, the patent provides new methods for treating kidney and pancreatic diseases or disorders using renalase polypeptides or other agents that target the PMCA4b pathway.

Problems solved by technology

Renal injury can lead to chronic kidney disease (CKD), which is associated with increased morbidity and mortality, is largely due to cardiovascular complications.
The presence of pre-existing CKD and end stage renal disease (ESRD) also predispose to acute pancreatitis and worsen its severity.

Method used

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  • Compositions and Methods for Treating and Preventing Pancreatitis, Renal Injury and Cancer
  • Compositions and Methods for Treating and Preventing Pancreatitis, Renal Injury and Cancer
  • Compositions and Methods for Treating and Preventing Pancreatitis, Renal Injury and Cancer

Examples

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experimental examples

[0227]The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0228]Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore, specifically point out the preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

example 1

Identification of a Receptor for Extracellular Renalase

[0229]The results described herein identify PMCA4b as a renalase receptor, and a key mediator of renalase dependent MAPK signaling. Using biotin transfer studies with RP-220 in the human proximal tubular cell line HK-2 and protein identification by mass spectrometry, PMCA4b was identified as a renalase binding protein. This previously characterized plasma membrane ATPase is involved in cell signaling and cardiac hypertrophy. Co-immunoprecipitation and co-immunolocalization confirmed protein-protein interaction between endogenous renalase and PMCA4b. Down-regulation of endogenous PMCA4b expression by siRNA transfection, or inhibition of its enzymatic activity by the specific peptide inhibitor caloxin1b each abrogated RP-220 dependent MAPK signaling and cytoprotection. In control studies, these maneuvers had no effect on epidermal growth factor mediated signaling, confirming specificity of the interaction between PMCA4b and renala...

example 2

Modulation of the Activity of PMCA4b Mediates Renalase's Cytoprotective Action

[0253]The effect of renalase on the ATPase activity of PMCA4b is examined, including its effect on Vmax, Km, and constitutive activation. The local and / or global effect of renalase's interaction with PMCA4b on calcium dynamics is also examined. Whether the disruption of the PMCA4b macromolecular complex with RAS SF-1 modulates the action of renalase (MAPK signaling and cytoprotection) is further examined. Whether PMCA4b knockout mice respond differently than wild type mice to renal ischemia or exposure to cisplatin is examined, as is whether renalase modifies the extent of renal injury.

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Abstract

The present invention includes compositions and methods for detecting, treating and preventing renal and pancreatic diseases and disorders.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority to U.S. Provisional Application No. 61 / 994,279, filed May 16, 2014, which is hereby incorporated by reference in its entirety herein.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under grants RC1DK086465, RC1DK086402 and R01DK081037, awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Renalase (also designated RNLS and gene C10orf59) is a novel secretory flavoprotein oxidase (Farzaneh-Far et al., 2010, PLoS One 5:e13496; Desir et al., 2012, J. Am. Heart Assoc. 1:e002634; Desir et al., 2012, 6:417-426; J. Am. Soc. Hypertension; Xu et al., 2005, J. Clin. Invest. 115:1275-1280; Li et al., 2008, Circulation 117:1277-1282). Single nucleotide polymorphisms present in the gene are associated with hypertension, cardiac disease and diabetes (Farzaneh-Far et al.,...

Claims

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Application Information

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IPC IPC(8): C12N9/02C12Q1/26
CPCC12N9/0036C12Y106/03G01N2333/90209A61K38/00G01N2800/06C12Q1/26C12N15/1137C12Y306/03008C12N2310/14A61P1/18A61P13/12A61P35/00A61P35/02A61P35/04A61P37/04A61P9/12
Inventor DESIR, GARY
Owner YALE UNIV
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