MEMBRANE DYNAMICS

The role of membrane trafficking in immune cell function

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 Obiettivo del progetto (Objective)

'Recently, receptor signal transduction has been identified to occur not only at the plasma membrane, but also at various intracellular compartments. Hence, receptor trafficking and signal compartmentalization may contribute to a higher level of cellular organization. The proposal’s objective is to understand fundamental principals in the regulation and biology of membrane trafficking and signal compartmentalization, and to test them in a physiological context. The overall research concept is to study two immune specific regulators for small GTPases, RIN3 and ACAP1, which are involved in the regulation of membrane trafficking and the actin cytoskeleton. In a functional genomic approach, mice deficient for these genes will be generated and lymphocyte signaling and immune cell function/development will be used as a physiological read out to study the biological role of signal compartmentalization. The analysis of knock-out mice will be complemented by biochemical in vitro experiments to further dissect molecular mechanisms of RIN3/ACAP1 function. In addition the potential role of these molecules in the development of immune disorders, such as allergy/asthma will be analyzed. Thus, the study will provide novel insights into the complexity of functions regulated by signal compartmentalization, may have far reaching implications for our understanding of immune cell function in health and disease, and may offer an opportunity to develop novel therapeutical strategies in autoimmunity. The researcher is an internationally experienced and well recognized expert for membrane dynamics and trafficking. The proposed theme regarding the physiologic relevance of membrane dynamics demonstrates a high degree of originality and innovation in a very promising research field. The host, the Research Center Borstel, is characterized by an interdisciplinary approach combining basic sciences with clinical research providing an ideal scientific environment to conduct the proposed work.'

Introduzione (Teaser)

Mast cells are connective tissue cells that play a crucial role in allergic and autoimmune diseases.

Descrizione progetto (Article)

The molecular mechanisms underlying the interaction of mast cell granules with plasma membrane are not well understood. 'The role of membrane trafficking in immune cell function' (Membrane dynamics) is a project that has set out to discover and test the primary factors involved in the regulation and biology of membrane trafficking and signal compartmentalisation.

Specifically, researchers are analysing the biological function of two regulators of small guanosine triphosphatases (GTPases), a large family of catalyst enzymes that separate the water molecules of guanosine triphosphate (GTP). These regulators are RIN3 and ACAP1 and are involved in membrane trafficking and the regulation of the actin cytoskeleton. The actin cytoskeleton is a dynamic network central to the movement and shape determination of cells.

In addition to studying the biological function of these molecules, project partners are also focusing on what role they play in the development of allergy/asthma and autoimmunity. In studies performed to date, the focus has been on analysing the gene expression profile of RIN3 and ACAP1 in immune cells.

Intricate gene expression studies using a mouse model revealed a high expression of RIN3 in mast cells and dendritic cells. However, while RIN3 was hardly detectable in other immune cells, ACAP1 gene expression was highest in T and B lymphocytes and also expressed in macrophages and dendritic cells.

Ongoing studies of RIN3 under varying circumstances reveal an inhibitory function on mast cell degranulation and identify it as a negative regulator of mast cell function. The research team has cloned murine RIN3 for future use in overexpression studies that aim to further define the cellular function of RIN3.

As work continues, Membrane dynamics is working to generate RIN3-deficient mice, which will open up new prospects of generating mouse disease models for research into allergy/asthma.