Project ID CM-HD2023_31

ThemeCM-HD

Co Supervisor 1A Immunobiology, SIMSWebsite

Co Supervisor 1B DIB, SIMSWebsite

Class A scavenger receptors (SR-A and MARCO) mediated lipid handling in macrophages- a mechanistic investigation

The class A scavenger receptors SR-A and MARCO are macrophage-restricted phagocytic receptors. They were discovered by their ability to take up oxidised lipids/lipoproteins (Ox-LDL) and develop lipid-laden foam cells in atherosclerotic plaques. However, they are also involved in the clearance of apoptotic cells, microbial pathogens and many other endogenous and exogenous ligands. Furthermore, whilst these two receptors play protective roles in various infectious and inflammatory/autoimmune disorders, they can also promote cardiovascular, metabolic and malignant diseases. However, the molecular basis for their opposing roles in different pathologies remains unknown.

We hypothesise that SR-A and MARCO remove oxidised lipids and maintain tissue homeostasis in the steady-state. However, in some situations, such homeostatic function becomes maladapted, contributing to the pathogenic processes. For example, we showed that SR-mediated lipid uptake in the tumour microenvironment induces tumour-promoting macrophages supporting tumour growth and metastasis.

Objectives:
1. To establish the mechanism of how SR-mediated uptake influences the downstream metabolism and recycling of oxidised lipids in macrophages
2. To determine how SR-mediated oxidised lipid uptake influences macrophage polarisation states, phenotypes and functions
3. To develop therapeutic strategies about how the SR-lipid axis can be targeted in different disease contexts

Techniques: isolation and culture of primary macrophage from WT and SR KO mice, differentiation of human iPSC-derived macrophage, CRISPR-based gene editing, bulk and single-cell RNAseq/ATACSeq, multiple functional and genomics assays, and bioinformatic analyses. Methodologies are already established, and appropriate training will be provided. We strongly encourage prospective candidates to contact us for an informal discussion to learn more about this project.

One representative publication from each co-supervisor:

https://doi.org/10.1084/jem.20210564
doi: 10.1016/j.cmet.2019.02.016.