Research

The mammalian brain is the most complex organ of all living organisms. The molecular machinery that regulates the generation of this enormous cellular complexity remains largely unknown. Our goal is to tackle this question by understanding the interplay between extracellular signaling cues and intrinsic gene regulation circuitries that control proliferation vs differentiation decisions in neural stem cells (NSCs) in health and disease. Elucidation of these mechanisms will not only provide insights into the basic principles of brain formation, but will also allow novel therapies for the treatment of brain-related diseases, tumors and traumas. To this end, our main lines of research are:

To unravel the role of novel gene regulation networks in neural differentiation
The current view in the field suggests that these regulatory networks act to subdivide the neural tube into defined progenitor domains and establish distinct differentiation programs in the neurons and glial cells that emerge from each domain. Failure of NSCs to make the correct specification choices at the appropriate time can result in severe developmental deficits, malformations, neurodegenerative diseases or cancers. Despite the wealth of information on the morphogens’ action in NSCs, little is known about the intrinsic gene regulatory networks that define neuronal and glial cell identity. The long term aim of our group is to understand the fundamental transcription regulation networks that control NSC differentiation and sub-type specification during development and adult life.

To decipher the role of long non-coding RNAs in mammalian brain development
With the advent of new generation sequencing technologies and exploration of the non-coding genome, a growing list of formerly unknown regulatory long non-coding RNA species (lncRNAs) have come into spotlight. Although thousands of lncRNAs are expressed in adult mammalian brain in a highly patterned and specific manner, they remain poorly characterized and their roles in brain development have not yet been studied. To explore the links between lncRNAs, brain development and brain-related diseases, we are extensively investigating the involvement of these molecules in the development of mouse brain.

To investigate the involvement of novel transcription regulators in nervous system-related diseases and cancers: focus on druggable factors
Neurological diseases/disorders are largely incurable and cause enormous personal suffering and substantial cost to society. According to WHO, dementia affects more than 35 million people worldwide and is expected to triple by 2050, while more than 300 million people of all ages suffer from depression, posing a severe threat to public health and healthcare systems in a global scale. The recent breakthrough discovery of the endogenous regenerative capacity of human brain has given new hope for the treatment of brain-related diseases. However, this ability is very limited and restricted to only few areas of the brain. Over the last few years there is an immense academic and biopharma/translational research interest in identifying new compounds with the capability to promote and extent the regenerative capacity of human brain. Despite the dramatic escalation in the research efforts and provided therapies, there are currently no highly effective medicines available to prevent or cure these diseases. These clinical observations underscore the need for novel therapeutic insights and pharmacological targets.

Our scope is to apply the knowledge acquired from our above-mentioned developmental studies to manipulate the proliferation, differentiation and survival properties of endogenous neural stem cells.  We strongly believe that these efforts could eventually contribute significantly to the development of novel therapeutic strategies for neurological diseases such as neurodegeneration, depression, dementia and brain traumas.

Along these lines, our second scope is to utilize the knowledge from our developmental studies in combating nervous system-related tumors, including pediatric neuroblastoma and glioblastoma. Our aim is to inhibit the growth and induce differentiation and/or apoptosis of neuroblastoma/glioblastoma cells by using small molecule agonists and antagonists of transcriptional regulators. These experiments could provide important information for early events in carcinogenesis and potential new targets for cancer therapy.

Unilateral over-expression of a GFP tagged transgene (Green) in the spinal cord of chick embryo by in ovo electroporation. The Red stain indicates the presence of post-mitotic neurons.

A chick spinal cord section stained for neurons (Green) and glial cells (Red).

In this image a section of a chick eye is shown.