DKK3 T2DM · Wnt agonist Dickkopf 3 (DKK3) is a type 2 diabetes susceptibility gene
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2010-09-01 → 2013-08-31
- Финансиране от ЕС
- 75 000 €
- Участници
- 1
- Схема
- MC-IRG
Линиите свързват координатора с партньорите.
Накратко на български
Генът Dickkopf 3 (DKK3) и неговата роля в развитието на диабет тип 2 се анализират чрез проучване на генетични вариации при различни групи хора. Това помага за разбирането на биологичните механизми, които правят някои хора по-податливи на това хронично заболяване.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Wnt agonist Dickkopf 3 (DKK3) is a type 2 diabetes susceptibility gene
To date, Type 2 Diabetes mellitus (T2DM) poses one of the major global health threats, affecting more than 250 million people worldwide. The diabetes epidemic is spreading so rapidly that by 2030, roughly one in 9 adults of the age of 30 will suffer from diabetes worldwide. In spite of all medical efforts, T2DM remains an incurable chronic disease with devastating complications such as loss of vision or amputation of limbs because of poor circulation. Over recent years, several genome-wide association studies (GWAS) set out to identify genomic alleles that lead to increased T2DM susceptibility. In spite of considerable investments, however, these genetic studies have so far been unable to elucidate defined biological pathways that are involved in the pathogenesis of the disease. The currently best-replicated T2DM susceptibility locus, TCF7L2, is a Wnt signalling component that binds beta-catenin and acts as a co-transcription factor for Wnt target genes. Similarities between diabetic retinopathy and Familial Exudative Vitreoretinopathy (FEVR, OMIM #133780) which has been linked to mutations in Wnt receptors Frizzled 4 (FZD4) and Low density lipoprotein-related receptor 5 (LRP5) further implicate defective Wnt signaling in T2DM. Moreover, defective Wnt signaling has been demonstrated for genes implicated in Bardet-Biedl Syndrome (BBS, OMIM #209900) in mice and zebrafish. Symptoms of genetically heterogeneous BBS include diabetes, truncal obesity and hypertension. These lines of evidence suggest that a subset of Wnt signaling components contributes to T2DM susceptibility. Out of five candidate Wnt genes, we observed a significant association with a SNP in the promoter region of Dickkopf 3 (DKK3) in two Chinese, one Japanese, and one Caucasian cohort. Other members of the Dickkopf family of genes have been described as Wnt antagonists which, when overexpressed, lead to a loss of beta-catenin dependent Wnt signaling. In contrast, overexpression of DKK3 had no effect on transcriptional activity in vitro. DKK3 has been named for sequence similarity only and because of the absence of the characteristic phenotype (enlarged head region), it had been suggested that DKK3 had no role in Wnt signaling. The main objective of this study is therefore, to characterize the role of DKK3 as a T2DM susceptibility gene and a regulator of Wnt signaling in beta-cells and pancreatic islets. We subdivided the main objective into several aims: Aim 1: To characterize Wnt signaling in beta-cells and pancreatic islets under specific consideration of the role of Dickkopf3. Aim 2: To characterize the role of Dickkopf3 in beta-cell and pancreatic islet function. Aim 3: To characterize the role of Dickkopf3 in pancreas formation. Aim 4: To characterize the T2DM susceptibility of Dkk3 mutant mice.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Type 2 diabetes mellitus (T2DM) is a complex genetic disorder of largely obscure etiology where alleles at numerous loci are thought to interact with environmental and stochastic cues to induce the phenotype. We have recently identified a T2DM susceptibility allele at the DKK3 locus. Using a combination of case/control association and functional studies, we demonstrated that the minor allele of SNP rs11022111 in the DKK3 promoter is significantly associated with T2DM in two Chinese and one Caucasian cohort and results in the disruption of a conserved SP1 binding site, leading to reduced DKK3 expression. We also showed that, in contrast to other members of the DKK family, DKK3 is a likely agonist of Wnt signaling (both canonical and non-canonical), in a Fz- and LRP6-dependent manner and regulates the expression of TCF7L2, another T2DM susceptibility gene. Our preliminary data implicate the regulation of Wnt signaling in the pathogenesis of T2DM. In this proposal, we hypothesize that aberrant Wnt signaling in the adult pancreas can lead to impaired glucose tolerance, insulin secretion and other diabetic phenotypes. To address how Dickkopf 3 influences Wnt signaling in β-cells and pancreatic islets as well as pancreatic islet functions, I propose to identify the subset of Wnt signaling components that are active in MIN6 cells and islets, to characterize the effect of impaired Wnt signaling on islet function and formation, and finally, to investigate the metabolic state of Dkk3-/- mice when challenged with a high fat diet.
Оригинален текст от CORDIS (на английски).
Участници
- KAROLINSKA INSTITUTET · STOCKHOLMКоординаторШвеция
Връзки
Данни: CORDIS, © Европейски съюз