Senior Research Associate, Univeristy of Cambridge
I investigate how the fetal brain develops during pregnancy
Despite improvement in survival rates of children who have sustained brain injury during fetal life or just after birth, there continues to be a diverse spectrum of cognitive and motor outcomes in survivors, thus placing a substantial burden on the nation’s health and wealth. In order to develop strategies for prevention or treatment, there is a need to understand the underlying mechanisms of brain injury resulting in neurological impairment.
Mitochondria are the powerhouses of all mammalian cells, including brain cells, which rely on mitochondrial energy production for survival. Recent advances in the field of mitochondrial biology has demonstrated that mitochondrial activities go beyond supplying energy to the brain. Indeed, in the developing brain, mitochondria appear to be commanders of inflammation, cell development and connectivity, and possibly repair after injury.
In many of the key tissues essential for neonatal survival, including the brain, there are maturational changes in the fetal tissues before birth in preparation for the functional changes at delivery. Hormones play an important role in the maturation of tissues essential for neonatal survival. Cortisol, a glucocorticoid, rises in concentration in the fetus towards birth and increases the activity of the thyroid hormone, tri-iodothyronine (T3). Cortisol and T3 induce tissue-specific maturation, both in combination and independently. Fetal glucocorticoid concentrations can also rise before term in response to adverse intrauterine conditions, such as a lack of oxygen (hypoxia), whereas fetal thyroid hormones are reduced in fetuses that are growth restricted or small for gestational age. To date, little is known about the normal development of mitochondrial function in the brain during the period before birth, and how the brain mitochondria prepare for the extra demands for energy after birth.
My research aims to establish the developmental and hormone regulation of mitochondrial function in the brain, by assessing mitochondrial function in different brain regions during development, and determining whether hormones can modulate cerebral mitochondrial function. Answering these questions will provide insight into the role of mitochondria in brain development as well as injury.
Abstract: Progress in the field of mitochondrial biology in the past few years has shown that mitochondrial activities go beyond bioenergetics. These new aspects of mitochondrial physiology and pathophysiology have important implications for the immature brain. A picture emerges in which mitochondrial biogenesis, mitophagy, migration, and morphogenesis are crucial for brain development and synaptic pruning, and play a part in recovery after acute insults. Mitochondria also affect brain susceptibility to injury, and mitochondria-directed interventions can make the immature brain highly resistant to acute injury. Finally, the mitochondrion is a platform for innate immunity, contributes to inflammation in response to infection and acute damage, and participates in antiviral and antibacterial defence. Understanding of these new aspects of mitochondrial function will provide insights into brain development and neurological disease, and enable discovery and development of new strategies for treatment.
Pub.: 25 Jan '14, Pinned: 29 Jun '17
Abstract: The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal growth and development of the fetus. Their bioavailability in utero depends on development of the fetal hypothalamic-pituitary-thyroid gland axis and the abundance of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive hormone. Fetal T4 and T3 concentrations are also affected by gestational age, nutritional and endocrine conditions in utero, and placental permeability to maternal thyroid hormones, which varies among species with placental morphology. Thyroid hormones are required for the general accretion of fetal mass and to trigger discrete developmental events in the fetal brain and somatic tissues from early in gestation. They also promote terminal differentiation of fetal tissues closer to term and are important in mediating the prepartum maturational effects of the glucocorticoids that ensure neonatal viability. Thyroid hormones act directly through anabolic effects on fetal metabolism and the stimulation of fetal oxygen consumption. They also act indirectly by controlling the bioavailability and effectiveness of other hormones and growth factors that influence fetal development such as the catecholamines and insulin-like growth factors (IGFs). By regulating tissue accretion and differentiation near term, fetal thyroid hormones ensure activation of physiological processes essential for survival at birth such as pulmonary gas exchange, thermogenesis, hepatic glucogenesis, and cardiac adaptations. This review examines the developmental control of fetal T4 and T3 bioavailability and discusses the role of these hormones in fetal growth and development with particular emphasis on maturation of somatic tissues critical for survival immediately at birth.
Pub.: 22 Mar '14, Pinned: 03 Jul '17
Abstract: An adverse foetal environment is associated with increased risk of cardiovascular, metabolic, neuroendocrine and psychological disorders in adulthood. Exposure to stress and its glucocorticoid hormone mediators may underpin this association. In humans and in animal models, prenatal stress, excess exogenous glucocorticoids or inhibition of 11β-hydroxysteroid dehydrogenase type 2 (HSD2; the placental barrier to maternal glucocorticoids) reduces birth weight and causes hyperglycemia, hypertension, increased HPA axis reactivity, and increased anxiety-related behaviour. Molecular mechanisms that underlie the 'developmental programming' effects of excess glucocorticoids/prenatal stress include epigenetic changes in target gene promoters. In the case of the intracellular glucocorticoid receptor (GR), this alters tissue-specific GR expression levels, which has persistent and profound effects on glucocorticoid signalling in certain tissues (e.g. brain, liver, and adipose). Crucially, changes in gene expression persist long after the initial challenge, predisposing the individual to disease in later life. Intriguingly, the effects of a challenged pregnancy appear to be transmitted possibly to one or two subsequent generations, suggesting that these epigenetic effects persist.
Pub.: 02 Jul '10, Pinned: 03 Jul '17
Abstract: Mitochondrial dysfunction has been increasingly linked to neurodevelopmental disorders such as intellectual disability, childhood epilepsy, and autism spectrum disorder, conditions also associated with cortical GABAergic interneuron dysfunction. Although interneurons have some of the highest metabolic demands in the postnatal brain, the importance of mitochondria during interneuron development is unknown. We find that interneuron migration from the basal forebrain to the neocortex is highly sensitive to perturbations in oxidative phosphorylation. Both pharmacologic and genetic inhibition of adenine nucleotide transferase 1 (Ant1) disrupts the non-radial migration of interneurons, but not the radial migration of cortical projection neurons. The selective dependence of cortical interneuron migration on oxidative phosphorylation may be a mechanistic pathway upon which multiple developmental and metabolic pathologies converge.
Pub.: 07 Apr '16, Pinned: 03 Jul '17
Abstract: Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging. Somatic mitochondrial DNA (mtDNA) mutations and respiratory chain dysfunction accompany normal aging, but the first direct experimental evidence that increased mtDNA mutation levels contribute to progeroid phenotypes came from the mtDNA mutator mouse. Recent evidence suggests that increases in aging-associated mtDNA mutations are not caused by damage accumulation, but rather are due to clonal expansion of mtDNA replication errors that occur during development. Here we discuss the caveats of the traditional mitochondrial free radical theory of aging and highlight other possible mechanisms, including insulin/IGF-1 signaling (IIS) and the target of rapamycin pathways, that underlie the central role of mitochondria in the aging process.
Pub.: 05 Mar '13, Pinned: 03 Jul '17
Abstract: Size at birth is a critical determinant of life expectancy, and is dependent primarily on the placental supply of nutrients. However, the placenta is not just a passive organ for the materno-fetal transfer of nutrients and oxygen. Studies show that the placenta can adapt morphologically and functionally to optimize substrate supply, and thus fetal growth, under adverse intrauterine conditions. These adaptations help meet the fetal drive for growth, and their effectiveness will determine the amount and relative proportions of specific metabolic substrates supplied to the fetus at different stages of development. This flow of nutrients will ultimately program physiological systems at the gene, cell, tissue, organ, and system levels, and inadequacies can cause permanent structural and functional changes that lead to overt disease, particularly with increasing age. This review examines the environmental regulation of the placental phenotype with particular emphasis on the impact of maternal nutritional challenges and oxygen scarcity in mice, rats and guinea pigs. It also focuses on the effects of such conditions on fetal growth and the developmental programming of disease postnatally. A challenge for future research is to link placental structure and function with clinical phenotypes in the offspring.
Pub.: 26 Mar '16, Pinned: 03 Jul '17
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