Kelli MacDonald (QIMR);
Jana Vukovic (UQ)
- Project level: PhD or Honours
Globally, haematological malignancies represent the fifth most commonly occurring cancers and the second leading cause of cancer death. Hematopoietic stem cell transplantation (SCT) is the most effective curative therapy, and the therapy of choice, for the majority of these cancers of bone marrow origin. The curative property of SCT lies in the graft-versus-leukemia effect which is required for ablation of residual cancer burden. This process is absolutely dependent on donor T cells contained within the graft, however these T cells are also the primary mediators of graft versus host disease (GVHD), a life threatening complication which significantly limits the success of SCT therapy. GVHD occurs in both acute (aGVHD) and chronic forms (cGVHD), which together contribute to the significant mortality and morbidity associated with SCT. Driven by the increasing prevalence and severity of cGVHD in clinical SCT patients, and the paucity of useful therapies for this disease, our research focuses on characterizing cGVHD disease pathology and delineating the underpinning pathophysiological mechanisms. Our overarching goal is to identify targets of intervention toward the development of much needed new therapeutics for cGVHD.
Chronic GVHD develops late after transplant (>100 days in patients) and presents with features that are overlapping with autoimmune diseases. Importantly, cGVHD has been shown to significantly impact neurocognitive function, which after SCT, is a serious cause of morbidity. Symptoms include memory impairment, depression and difficulty in performing multiple tasks simultaneously all of which adversely affect the patient’s quality of life. While the skin, lung and salivary glands are commonly effected tissues, studies in both patients and mice, have demonstrated the central nervous system (CNS) itself as a cGVHD target organ. Although CNS GVHD is recognized, to date, very few studies have been undertaken to identify the immune mechanisms driving pathology and neurological consequences. Our earlier studies have identified CSF-1 dependent macrophages as critical mediators of cGVHD in multiple target organs including the skin and lung. We now have preliminary data which demonstrates significant alterations in the brain macrophage (microglia) number and activation state with an associated decline in neurogenesis in transplanted mice that develop cGVHD. Notably, microglial activation is broadly implicated in both neuroprotection and neurodegeneration.
In mice, neurogenesis occurs predominantly in the hippocampus and in the subventricular zone (SVZ) of the lateral ventricle. The hippocampus plays important roles in memory, navigation and learning. Microglia play important roles in the CNS at steady state and are increasingly recognized to modulate hippocampal neurogenesis.
The aims of this project are to:
- Characterize the microglial populations in the hippocampus of cGVHD vs non-GVHD mice in terms of number, morphology and transcriptome.
- Confirm the impact of CNS cGVHD on neurogenesis.
- Examine the impact of CNS cGVHD on cognitive behaviour.
- Perform microglial depletion studies to confirm the direct role of microglia in altered neurogenesis and cognitive behaviour.
This is a challenging project for which the student will have a unique opportunity to undertake research across two fields: Transplant Immunology and Neuroscience in leading labs in both areas. Through these studies, the student will gain significant expertise in animal handling, transplant models, flow cytometry, immunohistochemistry, imaging and quantification, RT-qPCR and assessment of animal behaviour.