CD49D IN DIABETES · Role of the alpha4 integrin (CD49d) in Type-1 Diabetes mellitus prevention and treatment
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2007-09-03 → 2011-09-02
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-IRG
Линиите свързват координатора с партньорите.
Накратко на български
Ролята на протеина alpha4 integrin при развитието на диабет тип 1 се изучава чрез генетично модифицирани мишки. Резултатите могат да помогнат за предотвратяне или забавяне на болестта чрез използването на съществуващи блокиращи антитела.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Periodic Report Summary 1 - CD49D IN DIABETES (Role of the alpha4 integrin (CD49d) in Type-1 Diabetes mellitus prevention and treatment)
A grant of EUR 100.000 was approved to explore the role of the alpha4 integrin in immune-mediated diabetes in sensitive mice, an accepted model of human type-1 diabetes. The working hypothesis is that alpha4 ablation will prevent or delay progression of diabetes, depending on the timing of gene ablation. The scientific plan was to breed mice (alpha4f/f, tie2-cre, Tam-cre) onto the NOD background until the 10th generation, then to test whether they were "pure" NOD, then to cross-breed the ablaters with the alpha4f/f mice to generate alpha4-/- offspring and alpha4 competent control litter mates. As proposed, three mouse strains (alpha4f/f, Tie2cre, Tamcre) were serially bred onto the NOD background, to generate mice in which conditional ablation, either constitutive (tie2-cre) or inducible (Tam-cre) of alpha4 in the hematopoietic lineage can be achieved. Genotyping was performed after each generation. In spite of some delays due to dystokia and perinatal death of litter and breeder, we have now reached the 8th generation (in some strains, the 9th generation). We have regularly tested functionality of the cre-recombinase, which is prone to epigenetic silencing, as well as the proneness of NOD breeders for diabetes. After the 10th generation we expect to have "pure" NOD mice which can then be used as founders for the proposed studies, which will start in the 2nd/3rd quarter of 2011. Potential impact: Provided that the hypotheses are correct, development of Type I diabetes could be prevented (secondary or tertiary prevention) with alpha4-blocking antibodies, which are commercially available, although not licensed for this indication. Type I diabetes is one of the most costly and long-term debilitating illnesses in the Western world. Mouse husbandry costs have exploded since the writing of the proposal, by more than 600% (from EUR 0.25 to EUR 1.89 per mouse per week), so that the entire funds from the IRG went to the breeding and re-orders of NOD breeders. Salary and reagent costs for the work up to now were offset from a start-up grant provided by the host institution (EUR 40.000/year). Overall the transition/re-integration of the beneficiary (HB) has been very successful. He has in the interim been awarded several more grants from research foundations (Krebshilfe, DFG, BMBF, LOEWE (Federal State of Hesse)) and industry, in support of his basic research and clinical research programs, for a total of EUR 1.3M (> EUR 300 K/annum). His laboratory currently consists of 4 full-time and 3 part-time scientists, excluding himself. He has been promoted to Department Head of the Cellular Therapeutics / Cell Processing Department at the host institution, and is now responsible for a team of 28 full-time equivalent staff and a budget in excess of EUR 4.5 million.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Type-1 Diabetes mellitus (T1D) is caused by destruction of insulin-producing tissues by autoreactive T lymphocytes, which leads to insulin deficiency. The high frequency of T1D, as well as the significant T1D-associated morbidity and the substantial burden from long-term sequelae despite state-of-the-art insulin substitution therapies underscore the urgency of developing causal treatments. Protection of remaining islet cell mass at T1D diagnosis and (potentially) subsequent islet cell regeneration could palliate or cure T1D and reduce long-term morbidity and mortality. The alpha-4 integrin is a dominant homing receptor for inflammatory lymphocytes, and blockade of alpha-4 adhesion is therapeutic in a variety of inflammatory conditions, including autoimmune diseases, in mice and humans. Thus continued substitution of anti-functional alpha-4 antibodies from birth could prevent T1D in the spontaneously diabetic NOD mouse. Such an approach is, however, not clinically applicable to patients, since the risk of T1D can not be predicted at birth. Therefore, we here propose to test the hypothesis that by ablation of alpha-4 integrin adhesion during pre-diabetes (normoglycemic insulitis) or during early diabetes (recent onset of hyperglycemia), the continued recruitment of autoreactive T-cells to inflamed pancreatic tissue might be arrested. It is proposed that this might protect the remaining insulin producing cells, and thus, depending on the regenerative capacity of the pancreatic islets, might prevent or delay T1D if initiated during pre-diabetes (secondary prevention) or cure or palliate T1D if initiated early after its onset (tertiary prevention). This hypothesis will be tested in a new genetic mouse model of inducible ablation of alpha-4 integrin in the NOD strain. Since human alpha-4 adhesion blocking drugs are already available, these studies are testing a modality with immediate potential as a treatment for newly diagnosed patients with T1D.
Оригинален текст от CORDIS (на английски).
Участници
- JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN · Frankfurt Am MainКоординаторГермания
Връзки
Данни: CORDIS, © Европейски съюз