Francesca-Fang Liao, PhD
Professor
Room 229 Translational Research Building
Email: fliao@uthsc.edu
Phone: 901.448.2752
Fax: 901.448.1822
Education
- 1986 B.A. Xiamen University, Xiamen, China (Biochemistry)
- 1993 Ph.D. Albert Einstein College of Medicine, New York, NY (Molecular Immunology and Cell Biology)
- 1994-1998 Postdoctoral fellow, The Rockefeller University, New York, NY (Cell Physiology & Immunology)
Research Interests
My research efforts integrate genetic, neurological, molecular and cellular means to study the mechanisms underlying the pathogenesis of Alzheimer’s disease (AD). AD is a progressive degenerative disease of the brain characterized clinically by gradual loss of memory and cognitive function and, ultimately, death. The goal of my research is to identify and characterize early molecular events contributing to the emergence of cognitive decline and to discover information critical for the development of therapeutic strategies for the treatment of this devastating disorder. Our most recent research has been focusing on the following areas:
I: Novel role of PTEN in Neurodegeneration
The precise mechanisms underlying chronic neurodegeneration are largely unknown. Aberrant cell cycle re-entry in mature neurons is frequently associated with degenerating neurons. The cells cycle hypothesis states that aberrant cell cycle re-entry contributes to the process of neurodegeneration. However, a direct proof of the causative role of the associated dysregulated cell cycle events is lacking. Research in my laboratory showed that PTEN, a key negative regulator of the PI-3K/Akt pathway and the best-known tumor suppressor, is also important in control of neuronal cell cycle events. Loss of PTEN is associated with degenerated neurons in AD brains. We are investigating potential mechanisms which may impair PTEN function in neuronal cells during early stage AD. Neuronal stress leads to post-translational modification of PTEN by a hitherto little appreciated biochemical mechanism, S-nitrosylation, triggered by elevated nitric oxide (NO).
We further showed that S-nitrosylation of PTEN can be functionally coupled to the ubiquitination of PTEN and its accelerated degradation via the ubiquitin-proteasome pathway. Since S-nitrosylated PTEN is detectable in early stage AD but not in normal brain, we hypothesize that S-nitrosylation-induced PTEN degradation is at least partially causative of AD progression. To test this hypothesis, we are currently undertaking lentivirus-mediated gene therapy to deliver PTEN to affected neurons in an effort to halt neurodegeneration in AD mouse models.
II: The Role of NO Signaling
The role of NO signaling in soluble oligomeric amyloid peptides-induced synaptic damage in AD Genetic, molecular and cellular evidence strongly support a causal role of amyloid β (Aβ) in AD pathogenesis. The concept of this “amyloid hypothesis” has been expanded by the recent finding that the soluble oligomeric forms of Aβ rather than the highly aggregated amyloid plaques selectively target synaptic activity. To better understand the mechanisms underlying this Aβ-induced synaptic damage, we apply soluble oligomeric Aβ to cultured neurons and rodent brains via intracerebral injection to establish models to study the molecular and cellular consequences of Aβ toxicity on synaptic activity, including synaptogenesis, long-term potentiation, gene expression and signaling mechanisms. We currently focus on insulin and its downstream PI-3K/Akt signaling pathways since impaired insulin signaling has recently been suggested to be the major factor underlying the Aβ-induced synaptic damage. Specifically, we are investigating how Aβ-induced changes in NO might affect S-nitrosylation of the protein components of the insulin and PI-3K/Akt signaling pathways. We will investigate the NO signaling events induced by synaptotoxic Aβand by neurotrophic insulin/BDNF, which are speculated to be qualitatively distinct. In particular, we will address how these molecules/pathways are differentially regulated by distinct NO signaling using various approaches including NO imaging in live neuron.
Lastly, we also assess potential protective effect of a new class of Hsp90 inhibitors in synaptic functions and investigate underlying mechanisms involving modulation on NO signaling.