Research Opportunities

Autism is diagnosed in males more often than in females, even after accounting for postnatal social factors, such as underdiagnosis, misdiagnosis, camouflaging and masking in females. This suggests that biological factors contribute to sex differences in autism likelihood.   Several lines of evidence support the case that prenatal sex steroid synthesis is altered in pregnancies that result in a later autism diagnosis. Mothers of autistic children also have significantly elevated rates of conditions and pregnancy complications linked to the endocrine system (e.g. polycystic ovary syndrome and gestational diabetes). However, the potential causes of prenatal endocrine disruption and their effects on brain development, remain unclear.   The placenta may be of particular significance in neurodevelopment, as it maintains endocrine homeostasis prenatally and regulates nutrient transfer to the fetus. Placental function is also sexually dimorphic, with placentas of male fetuses producing more steroid hormones, fewer vascular protective factors and adapting differently to prenatal complications. Thus, the placenta could act as a mediator of various autism likelihood factors.  

To investigate how placental biology contributes to autism in a sexually-dimorphic manner, the Autism Research Centre is in the process of creating the first Autism Placenta Biobank, in collaboration with two specialist institutions: the Centre for Trophoblast Research in Cambridge (CTR), and the Tommy's Maternal Health network of the University of Manchester. This entails actively recruiting pregnant women with a first degree relative or child with autism, assessed through a screening questionnaire during pregnancy and asking them to donate their placentas to research. These are then compared to placentas from typical male and female pregnancies, where the pregnant woman has no first degree relative with an autism diagnosis.  

A successful PhD candidate will be included in this team of researchers and assist with:
1.    Recruiting participating women in Manchester and arranging for tissue transfer in Cambridge and the affiliated laboratories for testing and analysis.
2.    Helping analyse tissue morphology and protein distribution differences in the placentas.
3.    Helping analyse genomic data from the placentas (both methylome and transcriptome) and integrating findings with existing resources regarding brain development (e.g. post-mortem brain transcriptome) and autism (e.g. lists of autism candidate genes, derived from sequencing or genotyping studies).
4.    Locating additional sources for placental tissue and establish research collaborations, in order to add to the Biobank and replicate findings.  

This PhD will be part of a wider, multi-disciplinary research initiative that aims to understand the role of sex differences in neurodevelopment and autism likelihood.

The placenta is the interface between mother and fetus, integrating signals between the two. There are also a number of pathways linking the placenta to development of the fetal brain, termed the “Placenta Brain Axis”. The placenta releases extra-cellular vesicles (EVs), but the role of these in the placenta brain axis is unknown. EVs are small membrane bound organelles that contain proteins, metabolites and RNA including miRNAs. Placental EV content is regulated in response to the maternal environment and therefore could mediate the known detrimental effects of an in utero obesogenic/diabetic environment on offspring brain development.

This project will explore the underlying mechanisms by which changes in placental EV content can influence the short- and long- term effects on fetal and offspring metabolism via the brain. The project will involve:
(1) profiling of the protein and miRNA content of placental EVs isolated from lean and obese murine pregnancies,
(2) a combination of in vitro and in vivo experiments to establish the functional consequences of the changes in placental EV protein and miRNA content and
(3) labelling of placental EVs to identify the parts of the brain that they fuse with.  

We have recently identified a human airway epithelial progenitor cell expressing high levels of the pioneer transcription factor ASCL1. Our data suggest that these cells are key progenitors during lung development, and we hypothesize that ASCL1 plays an important functional role. We have recently constructed a single cell RNAseq atlas for the developing human lung and predicted the differentiation trajectories (He et al. 2022), many of which differ to those seen in mice. We have also established a human foetal lung organoid system in which the progenitor cells generate heterogeneous progeny (Lim et al., 2023). This organoid system provides an ideal, dynamic model to test hypotheses regarding lineage relationships and progenitor cell function during human lung development.   We will test the hypothesis ASCL1 is necessary for efficient airway differentiation. We propose to use our lung organoid systems, in conjunction with an effective genetic toolbox recently established in our lab for human organoids (Sun et al. 2021) to knock-down ASCL1 transcription. We will also use targeted damID (Southall et al., 2013; Sun et al., 2022) to assess the binding targets of ASCL1 in progenitor cells and during the differentiation of specific lineages.    

He et al., 2022. “A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates.” Cell 185: 4841-4860, doi.org/10.1016/j.cell.2022.11.005  

Lim et al., 2023 “Organoid modelling of human fetal lung alveolar development reveals mechanisms of cell fate patterning and neonatal respiratory disease.” Cell Stem Cell, 30: 20-37, doi.org/10.1016/j.stem.2022.11.013

Southall et al., 2013. “Cell-type-specific profiling of gene expression and chromatin binding without cell isolation: assaying RNA Pol II occupancy in neural stem cells.” Dev Cell, 26: 101-112, doi.org/10.1016/j.devcel.2013.05.020

Sun et al. 2021. “A Functional Genetic Toolbox for Human Tissue-Derived Organoids.” ELife 10 (October). https://doi.org/10.7554/eLife.67886  Sun et al., 2022. “SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling.” EMBO J, 41, e111338, doi.org/10.15252/embj.2022111338

Our group investigates embryonic mechanisms of cardiovascular development, to inform cardiac regenerative strategies, through reactivating of developmental processes in the adult heart1. The epicardium plays a crucial role in the embryo, to stimulate growth of the coronary vasculature and maturation of the myocardium (1). A key first step is epithelial to mesenchymal transition (EMT) to yield migratory cells which invade the myocardium and secrete potent paracrine factors. The adult mammalian epicardium is reactivated in response to myocardial infarction and contributes to repair (2), albeit sub-optimally, a major limitation being the extent of endogenous EMT. Based on our knowledge of ‘optimal’ embryonic mechanisms, we seek to enhance epicardial-based regeneration of the injured adult heart. Our preliminary data suggest a novel cell cycle-dependent mechanism controlling EMT and differentiation of epicardial cells, in line with the emerging paradigm of cell cycle control of stem cell fate (3). We will explore this exciting hypothesis by assessing how pharmacological and genetic perturbation of the cell cycle impacts EMT and fate, using functional assays, candidate and unbiased (e.g. RNA-Seq) approaches in cell culture, primary explant and genetic mouse models.

1). Redpath and Smart (2020). Stem Cells Transl Med. doi.org/10.1002/sctm.20-0352.

2). Smart et al. (2011) Nature. 474(7353):640-4.

3). Pauklin & Vallier (2013) Cell 155, 135.

Maternal over-nutrition and obesity during pregnancy is known to have long-term effects on the health of the offspring, including increased risk of obesity. Weight gain in offspring exposed to maternal over-nutrition is at least in part caused by hyperphagia- implicating altered function of hypothalamic energy homeostatic pathways as an underlying cause- but the precise mechanisms by which the in utero environment impacts on hypothalamic development is unclear. Key metabolic hormones such as insulin, leptin and ghrelin have a dual role during brain development as growth factors. These metabolic hormones are altered in an obese pregnancy, providing a direct route by which the maternal nutritional state can impact on offspring hypothalamic development. We will use a combination of in vivo manipulation of hormone levels (e.g. fetal brain injection) and ex vivo neuro-developmental techniques (e.g. neurospheres) to examine the consequences of altered metabolic hormone levels for early hypothalamic development. We will also use immunofluorescence and viral tracing to study hypothalamic architecture in the offspring of obese mothers once they reach adulthood, and correlate the anatomy with functional readouts of complex feeding behaviours using operant and metabolic chambers.

During pregnancy, nutrients must be supplied to the fetus for growth but also to the mother to maintain the pregnancy. This nutrient balance depends on the placenta, an organ that develops during pregnancy to transfer nutrients to the fetus and that secretes hormones into the mother with metabolic effects. Impaired placental function disrupts the materno-fetal nutrient balance and results in major pregnancy complications, including abnormal birthweight with both immediate and long-lasting effects on offspring health. However, our understanding of the importance of placental endocrine function in the control of fetal growth and long-term health of the offspring is unknown. To address this knowledge gap, we have developed new and robust models of genetically-induced placental endocrine malfunction in mice. Using these models, we have found that placental endocrine malfunction is associated with programmed changes in insulin and glucose handling of both the female and male offspring in adult life.

This PhD will extend these important findings by:
1. Identifying which tissues in the offspring are affected by placental endocrine malfunction and responsible for the altered glucose and insulin handling of offspring in later life.
2. Exploring the intrauterine mechanisms by which metabolic organs of the developing offspring are programmed by placental endocrine malfunction.

This will be achieved by studying the function of key metabolic organs in female and male offspring that were supported by placentas with endocrine malfunction. Particularly, it will use genetic manipulation and a range of in vivo physiological (metabolic testing, NMR scanning), and in vitro molecular (respirometry, RNAseq, western blotting, qPCR, epigenetic analysis), histological and biochemical assays.

The posterior Lateral Line primordium is a group of about a hundred cells that migrates under the skin, from the ear to the tip of the tail, periodically forming and depositing sensory organs called neuromasts, to spearhead formation of the zebrafish Lateral Line sensory system. In recent years, this relatively simple and accessible system has emerged as an attractive model for understanding various aspects of morphogenesis in the developing embryo, including the guidance of cell migration, tissue patterning and organ formation. The goal is to use a combination of cellular, molecular, genetic and biomechanical manipulations coupled with live imaging, image processing and the development of multi-scale computational models to understand the self-organization of cell-fate, morphogenesis and migration of the lateral line primordium. Specific focus will be on developing tools and methods for investigating, imaging, quantifying and modelling the mechanics of collective migration, morphogenesis of epithelial rosettes and the intercellular and intracellular signaling networks that coordinate lateral line primordium development.