Epigenetic mechanisms regulating pluripotency from embryonic to adult neurogeneisis

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Neurological diseases are amongst the most devastating since the brain does a very poor job in healing itself. In the large majority of cases, new nerve cells cannot be produced to replace injured tissue. With the increase in the population's average age, diseases such as Alzheimer's, Parkinson's and stroke will take an increasingly burdensome toll on individuals, families and society. Hope for a therapeutic solution has arisen with the discovery of brain stem cells and increased understanding of how they are controlled. Stem cells are found in two specific regions of the brain and continue to generate nerve cells in those restricted areas. Our goal is to understand how to enhance this process and entice it to be of more general relevance throughout the brain. In the past decade, laboratories around the world including ours (Shen in Beijing, Szele in Oxford) have discovered many molecules that stimulate stem cells to grow during normal development and molecules that stimulate them to repair a damaged brain. Use of this knowledge will allow us to develop medicines that mimic these molecules and thereby stimulate the growth of stem cells for brain repair. Since the repair of the adult brain is conceptually similar to the development of the brain, we also seek to understand fundamental molecular mechanisms regulating the generation of nerve cells from human embryonic stem cells (hESC). Amazingly, hESC can be grown in cell culture dishes, allowing us to discover molecules that increase nerve cell production. Similarly, adult brain stem cells can be grown in cell culture to study their generation of nerve cells. In this grant, we will use and compare both approaches in our goal to increase stem cell-derived nerve cell generation.Most research in the 20th century has uncovered how individual molecules regulate stem cells one at a time. In this century, a shift in emphasis has occurred, and the field is now seeking to understand how molecules work together to coordinate stem cell nerve generation. This is an intelligent shift since dozens to hundreds of molecules usually are required to coordinate stem cell nerve generation. But how are so many molecules regulated in the same space and at the same time in such a coordinated way? The answer is in a fashion analogous to how a conductor organizes an orchestra: she may increase the loudness of the string section whilst repressing the horns. So-called "epigenetic" mechanisms coordinate dozens to hundreds of molecules by causing some to be emphasized and some to be repressed. Epigenetic mechanisms can turn molecules completely on or off, or they can more subtly turn them up or down. Importantly, they do this in stem cells and thereby cause the cells to either proliferate or to turn into nerve cells.In our laboratories, we study how epigenetic mechanisms increase nerve cell production from embryonic stem cells (Shen, Beijing) and from adult brain stem cells (Szele, Oxford). In this collaborative project, we will seek to understand the extent to which the same molecules govern nerve cell production in the embryo as we as in the adult. We will also use this novel molecular knowledge to increase stem cell-mediated nerve cell production in a model of stroke. Brains of infants have a far higher plasticity than those in the adult and aged population. However, even infant brains do not completely repair themselves in diseases such as cerebral palsy. Thus, we will also seek to understand how epigenetic molecules enhance stem cell-mediated repair of a model of infant cerebral palsy.Our overarching goal is to eventually use this information to increase nerve cell production from stem cells. This exciting branch of regenerative medicine is one of the best hopes for the future of treating neurological disorders.