Animal model for identifying a common stem/progenitor to liver cells and pancreatic cells

• US 6,242,666 B1
• Filed: 12/16/1998
• Issued: 06/05/2001
• Est. Priority Date: 12/16/1998
• Status: Expired due to Fees

• Current Assignee: The Scripps Research Institute
• Original Assignee: The Scripps Research Institute
• Inventors: Krakowski, Michelle L., Kritzik, Marcie R., Sarvetnick, Nora
• Primary Examiner(s): Hauda, Karen M.
• Assistant Examiner(s): Woitach, Joseph T.
• Application Number:
  US09/212,531
• Time in Patent Office: 902 Days
• Field of Search: 800/8, 536/23.1, 514/44, 435/320.1, 435/455
• US Class Current: 800/18
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/03 Animal model, e.g. for test or diseases
• CPC Class Codes: A01K 2267/0325 Animal model for autoimmune diseases
• CPC Class Codes: A01K 67/0271 Chimeric vertebrates, e.g. comprising exogenous cells
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: A61K 38/1808 Epidermal growth factor [EGF] urogastrone
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 2501/11 Epidermal growth factor [EGF]
• CPC Class Codes: C12N 2501/117 Keratinocyte growth factors (KGF-1, i.e. FGF-7; KGF-2, i.e. FGF-12)
• CPC Class Codes: C12N 2503/00 Use of cells in diagnostics
• CPC Class Codes: C12N 2517/02 Cells from transgenic animals
• CPC Class Codes: C12N 2830/008 : cell type or tissue specific enhancer/promoter combination
• CPC Class Codes: C12N 5/0672 : Stem cells; Progenitor cells; Precursor cells; Oval cells
• CPC Class Codes: C12N 5/0676 : Pancreatic cells
• CPC Class Codes: C12N 5/0678 : Stem cells; Progenitor cells; Precursor cells
• CPC Class Codes: G01N 33/5005 : involving human or animal cells immunoassay G01N33/56966; immunoassays of protozoa G01N33/56905; protozoa in screening assays C12Q1/025
• CPC Class Codes: G01N 33/566 : using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds

Abstract

The invention provides animal models, where the ectopic expression of KGF, EGF, or both is under the control of a pancreas-specific promoter, e.g., the insulin promoter. The expression of KGF in the ins-KGF pancreatic islets of Langerhans results in enlarged islets, with substantial proliferation of duct cells within the islet mass, and the presence of albumin and alpha-fetoprotein-producing hepatocytes in the islets of the ins-KGF pancreata. The compositions and methods disclosed are useful for identifying and isolating pancreatic stem/progenitor cells, including a common stem/progenitor to liver cells and pancreatic cells.

Claims

1. A transgenic mouse having incorporated into its genome a polynucleotide sequence comprising a human insulin promoter operably linked to a keratinocyte growth factor (KGF)-coding polynucleotide sequence, wherein said KGF-coding polynucleotide sequence is expressed in the pancreatic cells such that said mouse exhibits in its pancreas at least one of the following morphological changes selected from the group consisting of hyperproliferation of duct cells and disorganized growth of islet of Langerhans.

3. The transgenic mouse of claim 1 further comprising incorporated into its genome a polynucleotide comprising a human insulin promoter operably linked to an EGF-coding polynucleotide, wherein said EGF-coding polynucleotide sequence and said KGF-coding polynucleotide sequence are expressed in the pancreatic cells such that said mouse exhibits in its pancreas at least one of the following morphological changes selected from the group consisting of hyperproliferation of duct cells, disorganized growth of islet of Langerhans, an increased number of intra-islet ductules, and extensive intra-islet fibrosis.

2. A transgenic mouse having incorporated into its genome a polynucleotide sequence comprising a human insulin promoter operably linked to an epidermal growth factor (EGF)-coding polynucleotide sequence, wherein said EGF-coding polynucleotide sequence is expressed in the pancreatic cells such that said mouse exhibits in its pancreas at least one of the following morphological changes selected from the group consisting of hyperproliferation of duct cells, disorganized growth of islet of Langerhans, and an increased number of intra-islet ductules.