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The role of apoptosis in mammary tissue regression

Reference	BB/C006836/1
Principal Investigator / Supervisor	Professor Richard Clarkson
Co-Investigators / Co-Supervisors	Dr Cristin PRINT
Institution	Cardiff University
Department	School of Biosciences
Funding type	Research
Value (£)	292,854
Status	Completed
Type	Research Grant
Start date	01/10/2005
End date	31/10/2008
Duration	37 months

Abstract

Apoptosis is essential for the efficient removal of superfluous cells during development and tissue morphogenesis. This is most evident in example of physiological tissue regression such as involution of the post-lactational mammary gland. In this study we address the possibility that physiological apoptosis has an additional role in regressing tissues, namely that apoptotic cells emit instructions to the surrounding tissue that initiate remodelling. Our first objective is to generate a conditional transgenic mouse line expressing an inhibitor of the core apoptosis machinery. This inhibitor, DQMB-CrmA, will be targeted to epithelial cells of the mammary gland using the MMTV promoter and will be expressed specifically during involution using the rtTA TetO tetracycline inducible system. Histological, molecular and transcriptome analysis of involuting mammary glands in these mutant mice will determine the extent of tissue regression in the absence of apoptosis. To further define the kinetics of this process, apoptosis will be inhibited both at the onset of involution and at the first signs of tissue remodelling (around 60hrs after weaning). We have previously hypothesised that two forms of apoptosis occur in mammary involution, the first example of differential use of apoptosis mechanisms in a physiological regression. Our second objective is to test this hypothesis by generating two additional transgenic lines expressing an inhibitor of extrinsic apoptosis (wtCrmA) and an inhibitor of intrinsic apoptosis (Bcl2), using the MMTV-rtTA system described above. We will study the rate of apoptosis, extent of restructuring and expression of remodelling-associated genes in these mutant mammary glands. The purpose of post-lactational involution of mammary gland is to remove superfluous secretary epithelial cells. Apoptosis clearly plays an important role in this process and our third objective is to assess the long-term consequences of inhibiting apoptosis. We will use the DQMB-CrmA transgenic line to persistently inhibit apoptosis throughout involution, and then we will study the development of the mammary gland during a subsequent pregnancy. Histological and molecular analysis of the mammary glands will determine whether appropriate ductal morphogenesis and alveolar differentiation has occurred. The generation of these transgenic lines will be a valuable resource both for further studies of the role of apoptosis in early mammary development and to the wider apoptosis community.

Summary

unavailable

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Ageing
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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