CSF1 and the control of postnatal growth and organ development in the rat

Lead Research Organisation: University of Edinburgh
Department Name: The Roslin Institute

Abstract

During pregnancy, many major organs of the body gain the many functions that will be necessary for life outside of the womb. Effects on growth at these early stages of life can have profound consequences for adult health. Most of the events that determine final body mass and function are controlled by protein found circulating in blood. This factor is called Insulin Growth Factor-1 (IGF1). Traditional knowledge indicates that this factor is made in the liver in response to growth hormone (GH) signals. We propose that this is not the entire picture and another factor ? Cytokine Stimulating Factor 1 (CSF1) - produced by the immune cells called macrophages contribute to the control the GH/IGF-1 system and thus contribute to the control of postnatal growth. We base this hypothesis on our data indicating that animals which lack CSF1 function have a range of developmental and growth abnormalities in common to animals deficient in GH/IGF-1. Although our preliminary data is compelling, the challenge remains to understand how these various factors interact to control growth. With this knowledge we will be better able to evaluate strategies to overcome growth impairment. To address these goals we aim to exploit new transgenic technologies in the rat. Specifically we will determine the consequence of reducing CSF1 signalling on growth and beneficial effects of elevating CSF1 levels as a possible treatment of impaired growth.

Technical Summary

In the third trimester of embryonic development, many major organs mature and develop functions that will be necessary for life outside of the womb. Most of the events that determine final body mass, as well as organ maturation, are controlled by Insulin Growth Factor-1 (IGF1). It is widely accepted that IGF1 is a circulating regulator produced by the liver in response to growth hormone (GH). We propose that through CSF1 activity macrophages contribute to the control the GH/IGF-1 system and thus contribute to the control of postnatal growth. Rats and mice that lack CSF1 signalling are macrophage deficient with many developmental abnormalities in common to animals deficient in GH/IGF-1 signalling. To confirm this view administering CSF-1 to new born mice had increased macrophage numbers and an overall increase of 30-40% in total body weight with corresponding enhanced maturity of organ function. Although this preliminary data is compelling, the challenge remains to understand the mechanistic regulation of the CSF-IGF-GH axis to underpin translation of this knowledge into application. To address these goals we aim to exploit new transgenic technologies in the rat to investigate the consequence of reducing CSF1 signalling on growth and elevating CSF1 levels as treatment of impaired growth. To do this we will exploit the lead position we have at The Roslin Institute in rat ES lines. Using this technology we propose to generate and evaluate both CSF1R-knockout and CSF1R-reporter rats to directly address these goals. This will provide a large animal model to evaluate CSF1-replacement strategies. There is a clear biological focus to this target in providing a basis for future therapeutic applications of CSF1 in humans, but it is also attractive as proof of concept for gene targeting in the rat system.

Publications

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Title Modified CSF-1 
Description A form of recombinant CSF-1 with much greater biological activity in vivo 
Type Of Material Technology assay or reagent 
Year Produced 2012 
Provided To Others? Yes  
Impact We believe it is will have significant clinical applications in tissue repair, based upon preclinical evaluation in mice and pigs 
 
Description Development of CSF1 as a therapeutic agent 
Organisation Pfizer Ltd
Department Pfizer Animal Health
Country Global 
Sector Private 
PI Contribution We have developed novel forms of CSF-1, new bioassays and tested them in mice, rats, chickens and pigs in various disease models
Collaborator Contribution They have produced materials for testing, and conducted parallel large-scale testing in animals
Impact Publications Patents
Start Year 2009
 
Description MRC Mouse Network 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution We participated as a Consortium in Innate Immunity and Macrophage Biology
Collaborator Contribution Produced joint funding application
Impact Submitted funding application rejected by MRC
Start Year 2011
 
Description Preclinical evaluation of anti-CSF1R 
Organisation Amgen Inc
Country United States of America 
Sector Private 
PI Contribution We have conducted ongoing research on the efficacy of antibodies against the CSF1 receptor in mouse models.
Collaborator Contribution Partners have provided large amounts of antibody
Impact Likely IP and commercial application, possible extension to veterinary species
Start Year 2007