H2020Индивидуална стипендия2016–2020

PRIISM-HD · Pathways Regulating Intramyocellular Insulin Sensitivity and Metabolism in Health and Disease

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2016-04-01 → 2020-11-11
Финансиране от ЕС: 255 350 €
Участници: 2
Схема: MSCA-IF-GF

Линиите свързват координатора с партньорите.

Накратко на български

Гени, които регулират метаболизма в черния дроб и усвояването на глюкоза в мускулите, се анализират чрез генетично редактиране. Това помага за разбирането на механизмите при диабет тип 2 и неалкохолно мастно дробно заболяване с цел откриване на нови терапевтични мишени.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Pathways Regulating Intramyocellular Insulin Sensitivity and Metabolism in Health and Disease

Currently, there is an urgent need to understand the pathogenesis of major metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Our research focuses on identifying new genes that control key metabolic pathways implicated in the pathogenesis of these diseases, with the ultimate goal of uncovering new therapeutic targets. Specifically, we are interested in how glucocorticoids regulate metabolism in the liver, and how insulin controls glucose uptake [GLUT4 trafficking] in skeletal muscle. Our approach harnesses whole-genome CRISPR-cas9 based technologies, which have transformed many areas of biological research since the discovery that the bacterial immune system could be re-engineered for gene editing in mammalian cells. Using both hepatocyte and myocyte cell-based models, we are employing this powerful genetic tool to simultaneously screen thousands of genes (on a genome-wide scale) for their involvement in these metabolic pathways. At the conclusion of this action, we have successfully identified 6+ genes not previously associated with regulating metabolism by glucocorticoids in the liver. Future experiments will involve further characterizing these genes and exploring their potential as new therapeutic targets for the treatment of NAFLD and T2DM.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Currently, there is an urgent need to understand the pathogenesis underpinning insulin resistance (IR) and type 2 diabetes (T2DM), due to their dramatically increasing prevalence. Glucocorticoids (GCs) are potent modulators of skeletal (Sk) muscle insulin sensitivity, as exemplified in patients with GC excess, Cushing’s syndrome, who develop IR and T2DM. Importantly, increased GC generation locally in muscle may contribute to the phenotype in T2DM patients. Although the precise molecular mechanisms driving IR in both T2DM and Cushing’s syndrome are unclear, dysregulated lipid metabolism is a common feature of insulin resistant muscle. This proposal aims to identify how GCs regulate intramyocellular lipid metabolism, and how this impacts on muscle insulin sensitivity. In addition, we will test a novel therapeutic target involved in mediating the metabolic actions of GCs, recently described by Dr Carolyn Cummins, the supervisor of the outgoing phase of this proposal. The complementary expertise in integrative molecular physiology of Dr Cummins, and of the Experienced Researcher, Dr Stuart Morgan, dovetail nicely within an established multi-disciplinary collaborative network of pharmacologists, molecular biologists and analytical chemists at the University of Toronto that have a unifying goal to uncover novel mechanisms regulating IR. Specifically, this proposal employs a systems approach by integrating both in vivo and in vitro pharmacological and genetic manipulation, with lipidomic/proteomic profiling and in-depth molecular characterisations. This novel strategy will significantly advance our understanding of key processes regulating insulin sensitivity in Sk muscle, a process essential for normal glucose homeostasis.

Оригинален текст от CORDIS (на английски).

Участници

THE UNIVERSITY OF BIRMINGHAM · BirminghamКоординаторОбединеното кралство
THE GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO · TorontoКанада