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Defining the Biology of Plasma Cells

Description 
Despite the fundamental importance of antibody secreting plasma cells (PC) in both health and disease, little is known about the factors and mechanisms that regulate their production, survival and ongoing function. For example, we don’t know why some plasma cells persist for decades in humans and others for months. Similarly, the criteria that determine PC retention are unknown and whether they vary according to tissue, pathogen or in autoimmune conditions where antibodies are the drivers of disease. Such information may provide not only insights into the biochemical processes supporting PC function and survival, but also reveal unique therapeutic approaches for manipulating plasma cells arising in autoimmune diseases and following vaccinations. To address issues of PC biology, we have created a 'purpose-built' mouse, which we are using to identify the cellular and molecular mechanisms of PC persistence and, for the first time, the unique properties of PC that persist from early life into old age or that arise during autoimmune diseases. This mouse strain has allowed us to define a gene signature of PC longevity, meaning that the role of specific gene products in PC production and/or persistence can now be tested. Overall, this work will produce a complete picture of the biology of these critical immune cells. There are three aims to this project: 1. Establish the mechanism of PC recruitment into survival niches. PC require external signals to survive and these signals come from a collection of cells termed the PC survival niche. It is proposed that there is a finite number of niches in the body and competition for access determines PC population turnover and equilibrium. We will rigorously test this theory by using the mouse we have developed for labelling cohorts of plasma cells and quantifying rates of decay in circumstances of varying competitiveness. If competition is the dominant factor driving turnover, what drives it and can it be manipulated? If competition is not the mechanism of turnover, then what is? 2. Establish the unique properties of ultra-long-lived plasma cells. By specifically labeling plasma cells that appear in the first weeks of life, we can uniquely identify them months or years later. Comparing those PC that have survived for many months to those freshly made will reveal the attributes of that persistence, including reactivity, functionality, gene expression and location. Determining these differences is fundamental to understanding PC biology. 3. Determine the function of specific genes in PC development and persistence. The roles of specific genes that are enriched for expression in long-term PC survival will be determined by inducing their deletion in emerging or established PC. We will achieve this aim by CRISPR/Cas9 targeting, Cre-induced gene deletion and drug inhibition of gene products. Relevant Literature: Peperzak et al., Nature Immunology (2013) 14:290-297 Shi et al., Nature Immunology (2015) 16:663-673 Zhang et al., J. Exp. Med. (2018) 215:1227-1243
Essential criteria: 
Minimum entry requirements can be found here: https://www.monash.edu/admissions/entry-requirements/minimum
Keywords 
Antibody, immune memory, cell survival, autoimmunity, physiology, pharmacology, microbiology, anatomy, developmental biology, molecular biology, biochemistry, immunology, human pathology, clinical
School 
Central Clinical School » Immunology and Pathology
Available options 
PhD/Doctorate
Honours
BMedSc(Hons)
Time commitment 
Full-time
Top-up scholarship funding available 
No
Physical location 
Alfred Research Alliance
Co-supervisors 
Dr 
Marcus Robinson

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