Neuroendocrine cells are a set of specialized neurons located in the hypothalamus. They are called neuroendocrine because rather than forming synapses with other neurons, their major function is to release their product, neurohormones, into the blood circulation to act on their endocrine targets. The neuroendocrine system consists of eight neuronal populations, each expressing a specific complement of neurohormones and receptors. They are important because they control most of our vital functions, such as growth, reproduction, nutrition, sleep, stress responses and homeostasis via hormonal balance. Moreover, the neuroendocrine hypothalamus is susceptible to a variety of developmental diseases or syndromes such as Kallmann’s, Prader-Willi, or Rubenstein-Taybi. Although neuroendocrine cells are an important component in the regulation of homeostasis and behavior, very little is understood about the mechanisms that control their differentiation. This is mainly due to a lack of an in vitro model of development.
The differentiation of embryonic stem cells in culture recapitulates a number of normal developmental processes that occur in mammalian embryos. This proposal aims at coaxing embryonic stem cells into becoming neuroendocrine in order to provide an in vitro model for further investigating the cellular and molecular mechanisms that control differentiation of hypothalamic neuroendocrine cells in early embryonic development. The biology of mouse stem cells mirrors that of human stem cells and, therefore, this work in mouse stem cells will ultimately provide a methodology for studying human embryonic stem cell differentiation into neuroendrocrine neurons, and thus serve as a means for therapeutic investigations.
Finally, this project will also provide the opportunity to generate a core of highly skilled undergraduate students trained to maintain and manipulate embryonic stem cells, who can use their skills in laboratories of both academia and biotechnology immediately upon graduation. This will provide them with critical skills in the expanding scientific field of stem cell biology research, to which the state of California is financially, politically, and socially dedicated.
The State of California and its citizens would benefit at two levels from this proposed work. The first is therapeutic and the second is educational:
1- Therapeutic benefits: Hypothalamic neuroendocrine cells are a set of specialized hormone-secreting neurons that integrate and control several homeostatic processes that are required for our survival. Disruption of the development of neuroendocrine systems thus has the potential of perturbing important physiological processes with lifelong consequences. However, little is know about the mechanisms that control the development of such a critical component of homeostatic and behavioral control. The success of this work with mouse stem cells will ultimately provide a template for research into the development of human neuroendocrine cells and, therefore, serve as a means for therapeutic investigations of a variety of neuroendocrine-related developmental diseases or syndrome, including obesity and high blood pressure.
2- Training of a skilled workforce in the field of stem cell research: This project will also be used as a template for semester-long individual projects in several upper division laboratory classes including cell and developmental biology, and research methodology classes that are part of our undergraduate curriculum. This project will, therefore, provide the opportunity to generate a core of undergraduates trained in techniques of stem cell culture as well as fluorescence microscopy imaging of cells, who can function in laboratories of both academia and biotechnology soon after graduation. In addition, embryonic stem cells are of great interest to science and medicine because of their potential use as a tool to grow and replace damaged tissues in regenerative therapies. Therefore, training my students to successfully grow, maintain and manipulate embryonic stem cells in culture will provide them with critical skills in the expanding scientific field of stem cell biology research, to which the state of California is financially, politically, and socially dedicated.