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Stimulation of pancreatic Beta cell proliferation

A technology of β cells and cells, which is applied in the field of stimulating the proliferation of pancreatic β cells, and can solve the problem of increasing the mass of total islets

Inactive Publication Date: 2009-08-19
THE ROCKEFELLER UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Glucose itself is known to stimulate β-cell replication, however, multiple of the above-mentioned mouse models have increased total islet mass prior to the onset of detectable hyperglycemia
Moreover, in most cases, the proliferative response did not correlate with hyperglycemia levels, suggesting that there may be glucose-independent factors promoting islet growth

Method used

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  • Stimulation of pancreatic Beta cell proliferation
  • Stimulation of pancreatic Beta cell proliferation
  • Stimulation of pancreatic Beta cell proliferation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] Tcf1 regulates the expression of a novel protein in pancreatic β cells

[0179] To identify mitogenic factors in pancreatic beta cells, Affymetrix TM Oligonucleotide expression assays comparing isolated Tcf1 - / - Gene expression in islets of wild-type sibling mice. The assay identified a gene encoding a transmembrane transmembrane protein (TMEM27) that expresses Tcf1 - / - Expression levels in mice were reduced 16-fold compared to controls. This result was confirmed by RT-PCR in an independent group of animals ( figure 1 a). To investigate whether Tcf1 is a direct activator of TMEM27 transcription, the TMEM27 promoter was analyzed and two conserved high-affinity binding sites were identified in its regulatory region ( figure 1 b). The human upstream regulatory region (SEQ ID NO: 10) and the mouse upstream regulatory region (SEQ ID NO: 11) comprise the Tcf binding site, starting at about -117 to about -102 in humans and mice, respectively (SEQ ID NO: 12 and SEQ ID NO...

Embodiment 2

[0182] TMEM27 expression is regulated during pancreatic development

[0183] Immunohistochemical analysis showing the pattern of TMEM27 expression during mouse pancreas development. In neonatal and adult pancreas, TMEM27 expression is restricted to beta cells of islets. During pancreatic development, TMEM27 is expressed at the earliest stages when hormones (mainly glucagon-positive cells) are positive. At embryonic stages E11.5 and E12.5, TMEM27 expression is localized in glucagon- and insulin-expressing cells. At the peak of endocrine cell expansion (from embryonic stage 13.5-18.5), TMEM27 coexists predominantly with glucagon until prenatal (E18.5), when it is also detectable in insulin-positive cells. In both neonatal and adult pancreas, TMEM27 was no longer detectable in islet α-cells and its expression was restricted to β-cells ( figure 2 ).

Embodiment 3

[0185] TMEM27 is an N-linked glycoprotein that forms dimers in vivo

[0186] TMEM27 contains two predicted N-glycosylation sites at amino acid residues 76 and 93, respectively. MIN6 cells were treated with tunicamycin, which inhibits N-glycosylation. Cells were incubated with increasing concentrations of tunicamycin, and protein extracts were prepared and analyzed by SDS-PAGE and Western blotting. After treatment with tunicamycin, the electrophoretic mobility of the two bands increased, while the high molecular weight protein disappeared ( image 3 a). This result was confirmed in an in vitro assay using N-glycanase, an enzyme that releases intact N-linked glycans. Western blot analysis of MIN6 cell extracts incubated with the enzyme showed similar results to tunicamycin treatment ( image 3 b).

[0187] A chemical cross-linking test was carried out to detect whether the TMEM27 protein existed as a multimer. MIN6 cell extracts were incubated in the presence of two differ...

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Abstract

This invention provides a polypeptide, TMEM27, and secreted forms thereof, nucleic acids and constructs encoding the same, and cells comprising the same. The TMEM27 protein is expressed in hormone positive cells at early stages of pancreas development and pancreatic ss-cells in the mature pancreas, whose expression promotes pancreatic ss-cell replication and increased islet mass. Applications of the protein in diagnostics and therapeutics are described.

Description

technical field [0001] The present invention provides a novel protein related to pancreatic beta cell proliferation and / or insulin secretion, nucleic acid and construct encoding the protein, and cells containing the nucleic acid and construct. The present invention also provides diagnostic and therapeutic applications of TMEM27 protein. Background technique [0002] Pancreatic β-cell proliferation is an important adaptive mechanism for maintaining euglycemia during physiological growth and obesity. Accumulating evidence indicates that β-cell mass is dynamic and that the requirement for insulin secretion increases during insulin resistance and pregnancy, which may cause rapid and pronounced changes in β-cell mass. β-cell mass is controlled by a balance between β-cell growth (replication) and β-cell death (apoptosis), however, the molecular basis of the factors that control β-cell mass remains to be elucidated. Understanding how β-cell mass is regulated is important for desi...

Claims

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Application Information

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IPC IPC(8): G01N33/53C12P21/06C12N15/00C07K1/00C07K14/00C07K17/00C07H21/04A61K38/16
Inventor 马库斯·施托费尔皮纳尔·阿克珀纳尔
Owner THE ROCKEFELLER UNIV
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