Novel strategies for therapeutic intervention of neurodegenerative diseases, brain tumors, mental retardation, and autism

Dr. Bonni's neuronal connectivity studies may lead to new therapeutic strategies for stalling the inevitable decline in cognitive and/or motor neuron function in neurodegenerative diseases and oxidative stress-related pathologies. Dr. Bonni's extensive research into the molecular networks that specify proper functioning of axons, dendrites, and synapses, and the overall neuronal circuitry, have uncovered crucial roles for several proteins. These include the MEF2 transcription factor family, involved in postsynaptic differentiation, and Cdh1-APC, a ubiquitin ligase that antagonizes axonal growth. These novel molecular targets may herald new therapies that prevent neuronal deterioration and possibly revitalize damaged neurons associated with neurodegenerative diseases.

Dr. Bonni’s research into the aberrant intracellular circuitry that occurs in brain tumors such as glioblastoma has significant commercial potential. Glioblastomas are typically aggressive and have a grave prognosis, with 5-year survival rates less than 5%. The lack of effective therapies suggests that companies interested in developing a new generation of cancer therapies may want to partner with laboratories performing high caliber translational research, in order to identify the elusive molecular mechanisms that glioblastoma cells pursue to thrive. Dr. Bonni’s laboratory is at the forefront of glioblastoma research, uncovering critical insights into oncogenic signaling in these cells, and consequently identifying novel molecular targets that may be viable candidates for designing small molecule chemical antagonists. The studies on the consequences of the genetic background of glioblastoma cells for mediating oncogenic signaling are especially compelling, and add a layer of “personalized” complexity that must be recognized in future efforts aimed at pharmacologic intervention.
 

Dr. Bonni is also poised to explore new approaches for addressing neruonal molecular processes that go awry in autism and mental retardation. Dr. Bonni is interested in identifying corporate collaborators that are interested in pursuing molecular and cellular studies into this prevalent disorder. 

Dr. Bonni’s research is centered around intracellular signaling mechanisms in neuronal cells, and how these signaling networks govern neuronal cell development as well as the malignant nature of transformed neural cells. Thus, Dr. Bonni’s lab is interested in piecing apart the molecular foundation of developmental pathways for neuronal cells and structures such as axons, dendrites, and synapses.

These studies are exploring intracellular signaling pathways in neuronal cells, and are linking postranslation modifications such as ubiquitination, acetylation, phosphorylation, and sumoylation to RNA transcription and apoptosis as well as neuronal cell remodeling, morphogenesis, differentiation, and regeneration.

Additionally, the lab is applying the insights gained from these studies to pathological conditions that afflict the CNS such as brain tumors. This “connecting the dots” between neural connectivity in cell and tissue development and disease pathology represents a major theme in Dr. Bonni’s research. 
 

Dr. Bonni’s research focuses on the molecular signaling pathways operating in normal neuronal cell growth and development as well as in pathological states such as glioblastoma, an extremely aggressive brain tumor. His studies have illuminated fundamental aspects of axonal growth, apoptosis of post-mitotic neurons, maturation and differentiation of dendrites, and suppression of interleukin-8-mediated glioblastoma growth. The studies on the intracellular regulation of brain tumors have reinforced the key biological paradigm of genetic and cellular context, in which a key signaling protein such as the transcription factor STAT3 can assume different functions depending upon the mutational status of proteins within the STAT3 “connectivity” circuit. The ramifications of these findings for therapeutic intervention are significant. In particular, the lab has discovered that downregulation of the tumor suppressor PTEN indirectly dampens the activation of STAT3 and thus interferes with a STAT3 tumor suppressor function: STAT3 was found to downregulate gene expression of the tumor promoting cytokine interleukin-8 gene. In stark contrast to this molecular itinerary, a different scenario ensues in cells harboring a deletion mutant of the epidermal growth factor receptor, designated as EGFRvIII. STAT3 associates with this EGFR isoform in the nucleus, conspiring to propel oncogenic signaling elicited by this aberrant receptor moiety. Taking these findings one step further, the lab elegantly demonstrated that the presence of EGFRvIII can override the STAT3 suppressor role, reprogramming the status of STAT3 into an oncogenic molecule.
 

Biological Mechanisms and Pathways

• Apoptosis •
• Astrocyte •
• Axon •
• Dendrite •
• Interleukin-8 •
• Nervous system •
• Neuron •
• Neuronal connectivity •
• Neuronal differentiation •
• Neuronal morphogenesis •
• Neuropathology •
• Oncology •
• Oxidative stress •
• Signal transduction •
• Sumoylation •
• Synapse •
• Tumor suppressor •
• Ubiquitination
•  

Cancer

• Apoptosis •
• Cancer •
• Glioblastoma •
• Oncology
•  

Disease Mechanisms

• Cancer •
• Glioblastoma •
• Personalized medicine
•  

Therapeutic Discovery Tools and Assays

• Cancer •
• Personalized medicine
•