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Studies on IAPP and Bri2- BRICHOS interactions in beta-cells.

Terrmin

HT25

Beskrivning

Titel Studies on IAPP and Bri2- BRICHOS interactions in beta-cells.
IAPP (islet amyloid polypeptide) is produced by the beta cells and secreted together with insulin upon stimulation. IAPP is a polypeptide hormone acting as a modulator for insulin. Amyloidosis is a group of protein misfolding diseases where misfolded proteins escaping degradation deposits as amyloid in various tissues.
Today, more than 35 unrelated proteins have been shown to misfold and deposit as amyloid in various organs, and each protein is associated with a specific disease. IAPP amyloid is a frequent finding in the islets of Langerhans in patients with type 2 diabetes, and in more recent studies IAPP amyloid has been detected in patients with type 1 diabetes. Human islets can be isolated from the pancreas and used for islet transplantation. This type of transplantation was suggested to be used as a treatment for insulin deficiency in type 1 diabetes. However, despite extensive work this has never been successful. One reason for this is the formation of IAPP amyloid in the transplanted islets. Formation of IAPP amyloid is cytotoxic and cause beta cell deathIslet transplantation was suggested to be a treatment for type 1 diabetes

A) Characterization of Bri2 expression and processing in ICCs
The expression and synthesis of Bri2 under normal and stressed conditions will be determined in ICCs. A comparison of the upstream regions of the IAPP and Bri2 genes reveals some similar regulatory regions and the effect on Bri2 expression during stress conditions (20 mM glucose, 1.5 mM palmitate, or a combination thereof) will be compared to the effects on IAPP expression.
This work will give information about differences and similarities in Bri2 and IAPP gene regulation.

B) Is the release of BRICHOS from Bri2 affected by metabolic stress?
We have data suggesting that processing of Bri2 by the convertases furin and ADAM10 and the release of the BRICHOS domain is necessary for obtaining an inhibitory effect on IAPP aggregation. The expression of Bri2, furin, and ADAM10 will be determined in ICCs cultured under metabolically stressed conditions and compared to control clusters cultured in 5.5 mM glucose using qPCR. At the same time, processing and release of the BRICHOS domain will be quantified in ICCs and in culture medium from ICCs using western blot with an antiserum that binds to an epitope present in BRICHOS and that detects both Bri2 (31kD) and BRICHOS (13kD).
This work will demonstrate the efficacy of Bri2 processing and reveal the amount of released BRICHOS present in or secreted from ICCs.

Huvudområde

Farmaceutisk vetenskap

Ämne

Fysiologi

Typ

Laborativ studie

Företag

Uppsala University

Ort/Plats

uppsala

Handledarens namn

Gunilla Westermark

Handledarens e-post

gunilla.westermark@mcb.uu.se

Institution

Institutionen för farmaceutisk biovetenskap

Program

Apotekarprogrammet

Kurs

Fördjupningsprojekt i fysiologi 30 hp - 3MC333

Omfattning/hp

30hp