We study the roles of brain insulin deficiency and insulin resistance in neurodegeneration. Three diseases of major interest to us are: Alzheimer's, alcoholic neurodegeneration, and fetal alcohol syndrome. Experimentally, we examine how insulin deficiency and/or insulin resistance leads to neuronal death, reduced energy metabolism, and decreased neurotransmission. We also investigate therapeutic measures to prevent or reverse brain abnormalities caused by insulin resistance (Type 3 diabetes).

1. Ethanol inhibition of insulin signaling in the brain. This research effort is to investigate the mechanisms by which chronic gestational exposure to ethanol causes neuronal death and contributes to cerebellar hypoplasia and microencephaly in fetal alcohol syndrome/fetal alcohol spectrum disorders. This research utilizes in vivo and in vitro experimental models and examines the effects of ethanol on insulin stimulated signaling through growth and survival pathways. The signaling pathways beginning with ligand-receptor binding down to the stimulation of genes required to promote survival and inhibit apoptosis are under investigation. The impairments in insulin signaling are being linked to abnormalities in neurotransmission and cognitive-motor functions. Finally, the mechanisms by which ethanol mediates these effects are under investigation.


2. Inhibitory effects of ethanol on neuronal migration in fetal alcohol syndrome. The goal of this research is to determine the mechanisms by which chronic gestational exposure to ethanol impairs neuronal migrain in the central nervous system. Our research led to the discovery that aspartyl-asparaginyl-b-hydroxylase (AAH) has a key role in neuronal migration and that ethanol inhibits the expression levels of AAH. We also determined that AAH is regulated by insulin and insulin-like growth factors (IGF). This research effort is structured to examine the insulin and IGF signaling pathways that regulate AAH expression and determine how ethanol inhibits the expression and function of AAH. This research utilizes in vivo and in vitro experimental models, and approaches such as gene silencing and gene over-expression. Recently, this line of research has been extended to characterize similar effects of ethanol on placental implantation and function. In addition, our research has demonstrated that the basic signaling pathways that mediate neuronal migration during development and placental implantation in utero are utilized by malignant neoplastic cells for metastatic growth.


3. Roles of brain insulin deficiency and insulin resistance in Alzheimer's disease. Our group discovered that in Alzheimer's disease, neurodegeneration correlates with brain insulin deficiency and brain insulin resistance. Since these intrinsic abnormalities closely resemble Type 1 and/or Type 2 diabetes mellitus, but occur in the absence of pancreatic disease, Type 2 diabetes, or metabolic syndrome, we coined the term, "Type 3 diabetes" to refer to the brain-specific form of diabetes associated with Alzheimer's. We demonstrated experimentally that brain insulin deficiency and insulin resistance produce a phenotype that closely resembles Alzheimer's, including amyloid accumulation and dementia. Therapeutic rescue measures are under investigation. In addition, studies are in progress to determine the degree to which other neurodegenerative diseases are associated with brain insulin deficiency or resistance.


4. Alcoholic neurodegeneration. This research project investigates mechanisms of neurodegeneration in human alcoholics. Taking advantage of prior knowledge gained from experimental models, we are able to characterize the effects of chronic ethanol consumption on the human brain and determine the degree to which cognitive impairment is related to brain insulin resistance. We are investigating the role of oxidative stress due to excessive formation of acetaldehyde as a mediator of neuronal death and neurodegeneration.

Research funding from the NIH, National Institutes of Alcohol Abuse and Alcoholism (NIAAA)
RO1: Study effects of ethanol on insulin signaling in the brain (2003-2008)
RO1: Study mechanisms of ethanol impaired neuronal migration (2003-2008)
K24: Mid-career mentoring award studying alcohol impairment of insulin signaling in human disease (2006-2011)

Harold G. Wolff Prize (1st place medical student research award)
1st Prize—senior medical student research
Stowell-Orbison Merit
Alzheimer Medal, 2000
Tan Yan Kee Award, 2005

American Association of Neuropathologists
American Society for Investigative Pathology
United States and Canadian Academy of Pathology
Society for Pediatric Pathology
American Medical Association
Rhode Island Medical Women's Association
Society for Neuro-Oncology

Bio 283: Molecular Pathogenesis of Disease-this seminar course covers what is currently understood about the molecular pathogenesis of several important diseases that affect Western societies, e.g. Alzheimer's, gastrointestinal malignancies, alcoholic liver disease, diabetes mellitus. Expert researchers in the field are invited to provide a didactic lecture (overview) and help lead an analytical discussion of assigned primary literature. Students are assigned primary responsibility for presenting the papers including critical data analysis. Students also generate their own reserach proposal concerning one of the topics discussed in the course.
Bio 195/196; My laboratory regularly hosts Brown undergraduate students who are guided to conduct independent research. In general, most students complete a summer internship (paid) to anchor the project before working in the lab during the academic year. Most students complete an honors thesis. In addition, students are assisted in the preparation of abstracts, oral presentations/posters, and manuscripts for publication and presentation.
Clinical Neuropathology: As part of the neuropathology training program at Rhode Island Hospital/Lifespan, I teach residents, fellows, and medical students clinical neuropathology, which includes review of human neuroanatomy. The residents and fellows are trainees in Neuropathology, Pathology, Neurology, Neurosurgery, or Psychiatry. Neuropathology conferences are held on a regular basis, 2-3 times per week, and represent a component of the overall Neuropathology training program.