Our genomes contain thousands of mobile DNA “jumping genes”, some of which can cause genetic mutations by copy-and-pasting themselves to new locations in our DNA sequence. Jumping gene mutations have long been known to cause genetic disease. More recently, jumping gene DNA and RNA molecules have been linked to autoimmunity and inflammation because they are recognised by the immune system as “non-self” nucleic acids, by pathways that normally combat viral infection. Jumping genes are highly active in placenta during pregnancy, but their impact in this tissue is not fully understood. 

This project will investigate whether too much jumping gene activity in placental cells can cause an inappropriate immune response, and how placental cells regulate jumping gene activity. This work will potentially reveal jumping genes as contributors to placental dysfunction and adverse pregnancy outcomes.

Background

High-grade serous ovarian cancer (HGSOC) accounts for 70% of all ovarian cancers and are highly aggressive and the second most lethal gynaecological malignancy worldwide. Resistance to standard-of-care platinum-based chemotherapy remains a major obstacle in clinical management of HGSOCs. Although initial response to chemotherapy is high (~80%), patients generally relapse within 18 months and eventually succumb to platinum-resistant disease. Hence, there is unmet need to develop an effective treatment for recurrent HGSOC patients, who otherwise have limited treatment options.
Metabolic alterations are linked to resistance to chemotherapies and targeted therapies in different cancers. Multiple and different traits, involving adaptations in both glucose and glutamine metabolism, and mitochondrial activity have been associated with platinum resistance in ovarian cancer cells. We have compelling data that broader inhibition of glutamine metabolism using a glutamine analogue 6-diazo-5-oxo-L-norleucine (DON) can sensitise chemo-resistant HGSOC to carboplatin. Hence, a more comprehensive inhibition of glutamine metabolism may represent an attractive strategy to overcome the rapid metabolic adaptation that leads to chemoresistance in HGSOC patients.
Over the past decade, immune checkpoint blockade (ICB) therapy has significantly improved long-term remission in patients with advanced skin, lung, and colorectal cancers. However, testing of immunotherapies in HGSOC has been disappointing, with modest 5%–15% response rates. Immune microenvironment of HGSOC is immunosuppressive due to presence of exceptionally high aneuploidy driven by copy number changes which can limit immunotherapy efficacy. Spatial transcriptomic profiling of infiltrated T and NK cells in HGSOC has revealed the presence of exhaustion markers, suggesting that tumour infiltrating effector T and NK cells are predominantly exhausted and lack cytotoxic functions. Moreover, HGSOC tumours are heavily infiltrated by immunosuppressive myeloid-derived suppressor cells (MDSCs), which may contribute to their poor response to immunotherapies. In triple-negative breast cancer (TNBC) cells, which are very similar to HGSOCs at the molecular levels, inhibition of the glutamine metabolism has improved cytotoxic function of infiltrating CD8+ T-cells, reduced the tumour infiltration of MDSCs and sensitized the tumours to ICB therapy. Hence, targeting glutamine metabolism may represent an effective therapeutic strategy to sensitize HGSOC tumours to ICB therapy.

Hypothesis

We hypothesize that broader inhibition of glutamine metabolism using a pro-drug version of glutamine analogue DON designated as DRP-104, may re-sensitize chemo-resistant HGSOC tumours to platinum-based chemotherapy by preventing the rapid metabolic rewiring that leads to drug resistance. Additionally, we hypothesize that glutamine inhibition using DRP-104 may alleviate immunosuppressive tumour microenvironment of HGSOCs by reducing MDSC tumour infiltration, activating effector T and NK cells, and may sensitize HGSOCs to ICB therapy. 

Aims

1. Examine the effect of glutamine inhibition in re-sensitizing chemo-resistant HGSOC tumours to platinum-based chemotherapy.
2. Deciphering the effect of glutamine inhibition on tumour immune microenvironment in HGSOC in vivo models. 
3. Evaluating the effect of DRP-104 in combination with ICB therapy in vivo.
    

The endoplasmic reticulum (ER) plays a crucial role in the production and presentation of MHC Class II antigens, which are essential for the immune system to recognize and eliminate foreign invaders. When proteins are misfolded or improperly assembled in the ER, it can trigger a cellular stress response known as ER stress. This stress can impact the generation and presentation of MHC Class II antigens in several ways. Our focus has been on antigen presentation by non-professional antigen presenting cells like epithelial cells. Project Aim: To investigate the complex relationship between protein misfolding, ER stress, and MHC Class II antigen presentation, with a focus on understanding how these factors influence the development of immune responses, particularly those involving CD4+ T cells.

Intestinal fibrosis is a significant complication affecting over 35% of patients with Inflammatory Bowel Disease (IBD), including Ulcerative  Colitis (UC) and Crohn's Disease (CD). Chronic inflammation within the intestinal tract triggers fibroblast overproduction of collagen, leading to luminal narrowing and obstruction. Despite advances in IBD treatment, the incidence of stricture formation remains high, indicating that current therapies may not adequately address the fibrotic process.

This research aims to elucidate the specific immune pathways that drive intestinal fibrosis in IBD. By understanding these mechanisms, we can develop novel inhibitory therapies to halt or even reverse the progression of fibrosis, improving the quality of life for patients with IBD

The IL-22RA1 receptor is abundant in the pancreas, and external IL-22 has been shown to improve pancreatic islet health and insulin secretion. However, the natural function of IL-22RA1 signaling within these cells is incompletely understood. Our recent work has shown that endogenous IL-22RA1 signaling in regulating insulin secretion, islet regeneration, and overall metabolic health. Understanding the specific mechanisms involved in IL-22RA1-mediated regulation of pancreatic beta cell function could lead to novel therapeutic strategies for diabetes and other metabolic disorders. This project will focus on investigating the exact mechanisms by which IL-22 regulates these processes, with a particular focus on calcium storage and cytoskeletal changes.

Inflammatory bowel diseases (IBD), which include ulcerative colitis (UC) and Crohn’s disease (CD), are chronic inflammation of the gastrointestinal tract. Anaemia represents the most common complication in IBD, prevailing in 27% of patients with CD and 21% of patients UC. Anaemia is associated with poor quality of life, increased rate of hospitalization and deaths in IBD. Anaemia in patients with IBD arise due to iron deficiency anaemia (IDA) and anaemia of inflammation (AI). Most anaemic IBD patients are treated with iron supplementation, but half do not respond to iron supplementation therapies. We have discovered that leaky gut (endotoxemia) plays a key role in IBD induced anaemia (Bisht et al, unpublished data). We showed previously (Bisht et al, Fron in Immu, 2020) that endotoxin receptor, TLR4, is expressed by erythroblastic island macrophages, a crucial immune cell supporting red blood cell formation. However, role of TLR-4 on IBD induced anaemia is poorly understood. In this project, we aim to explore the role of TLR-4 on iron homeostasis in mouse model of colitis.  We will specifically delete TLR-4 in erythroblastic island macrophages and tissue iron, iron homeostasis genes and proteins will be analysed.

The project will utilise mouse model of experiment colitis and mouse model of endotoxemia. Iron in liver, spleen and bone marrow will be analysed by Prussian blue and bathophenanthroline. Serum iron will be analysed using ELISA kit. Iron homeostasis genes in bone marrow, liver and duodenum will be analysed by quantitative real-time polymerase chain reaction.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and is characterized by a lack of estrogen, progesterone and human epidermal growth factor receptor (EGFR) expression. TNBC is more likely to recur than the other two subtypes and one of the primary challenges to treat TNBC is its intra-tumoral heterogeneity (ITH). Recent evidences have shown that these micro-environmental differences led ITH creates hurdles for effective therapy response. In this project, we discuss the evidence of intratumoral heterogeneity and its impact on the disease progression including sensitivity to different treatment options particularly chemotherapy and immunotherapies (PD1/PDL1 based). In this project, we aim to evaluate this Intra-tumoral heterogeneity of TNBC through next-generation patient-derived 3D tumour organoid and explant models, which can effectively expedite preclinical responses towards immune-antibody-directed therapies.

Transcription factors are the master regulators of cell state and, as a result, they play a fundamental role in disease. Despite their importance, transcription factors have traditionally remained largely refractory to therapeutic targeting. This project will leverage recent advances in CRISPR and mRNA technology to attempt to understand, then disrupt, the regions required for transcription factor activity. This could open up a new class of drugs that enable us to control the factors that control the identify of our cells.