Neurological Diseases Core     

Directors: Nancy Fiedler, PhD and Kenneth Reuhl, PhD

Members:

• Emmanuel DiCicco-Bloom, MD
• Lawrence Golbe, MD
• Alexander Kusnecov, PhD
• Michael Lewis, PhD
• Kiran Madura, PhD
• Oleg Mirochnitchenko, PhD
• Jason Richardson, PhD
• Eric Richfield, MD PhD
• Thomas Rugino, MD
• Patricia Sonsalla, PhD
• Mona Thiruchelvam, PhD
• George Wagner, PhD
• Gail Zeevalk, PhD
• Renping Zhou, PhD

 

Overview:
The vulnerability of the nervous system to chemical injury resulting from exposure to even extremely low levels of toxicants is well recognized.  Neural tissues often exhibit distinct patterns of cell-specific response to injury (a phenomenon termed ‘pathoclisis’), and unusual susceptibilities during the periods of pre-/postnatal development and advanced age. Elucidating the factors conferring these unique patterns of toxic response and their behavioral consequences represents the unifying theme of the Core.

Overall Goals:
The overall goal of the Core is to develop a mechanistic understanding of the factors that govern the response of the nervous system to toxic insult. The Core examines interactive contributions of chemical exposures and risk modifiers such as stress, gender, and developmental age to the pathogenesis of neurodegenerative diseases and developmental disorders.  Research focuses on: 1) development of mechanistically-based experimental models of toxicant-induced brain injury; 2) translation of findings from disease-relevant animal models to clinical and epidemiological studies; and 3) development and validation of biological response indicators for translation to human studies.

The Neurological Diseases Core integrates our long-standing basic research strengths with those of established clinical collaborators. The Core includes two working groups: 1) Neurodegenerative Diseases and 2) Developmental and Behavioral Disorders.  These two themes focus the expertise of the Core and integrate research disciplines ranging from basic neurosciences through public health interventions. 

Goals for the Neurodegenerative Disease Working Group:

Short Term:

• Develop and refine novel cell and animal models possessing specific genetic manipulations or toxic exposures leading to expression of a PD phenotype.
• Use genetic variants identified in human cell lines and animals to study the metabolism and excretion of environmental agents known to target the dopaminergic system.
• Study neuroinflammatory mechanisms of dopaminergic pathway damage and neuronal death.

Long Term:

• Establish a national repository of lymphoblast cell lines from L. Golbe’s PD patients. The repository will be housed within Rutgers University Cell and DNA Repository (J. Tischfield). Samples are available from ~1500 patients seen annually in his Movement Disorders Clinic.
• Develop genetically-engineered mouse models to test hypotheses regarding gene-environment interactions of PD and other neurodegenerative conditions. 
• Determine the role of susceptibility factors such as gender and age on PD in murine models
• Evaluate possible protective strategies, including dietary antioxidants, for a more complete        understanding of the biological risk factors in PD.

Goals for the Developmental and Behavioral Disorders Working Group:

Short Term:

• Determine the role of early developmental toxicity on subsequent patterns of behavioral development.
• Use biologic samples (blood, hair, urine) for assessment of toxicant exposure from ‘at risk’ cohorts enrolled in long-term studies of cognitive and behavioral function and from inner city infant cohorts.
• Use ongoing cohort studies to incorporate preliminary toxicant exposure data into risk models for behavioral dysfunctions such as impulsivity and risk-taking behaviors. 
• Identify key molecules in critical morphogentic pathways that are susceptible to xenobiotic disruption.

Long Term:

• Expand cohorts of mothers and infants with elevated exposure to lead, other toxicants and different stress histories to assess behavioral outcomes, including cognitive dysfunction and attention deficit, as well as stress responsivity and HPA axis function. These studies will allow direct translation of ongoing experimental studies which show gender differences in toxicant-stress interactions.
• In partnership with the National Children’s Study (Queens Vanguard Center), investigate associations between exposure to neurotoxicants and diagnosis of congenital malformations, learning disabilities, ADHD, and autism.
• Identify dietary interventions that ameliorate developmental effects of neurotoxicants.
• Core research related to neurotoxicant exposures (e.g., lead and solvents) and diseases (e.g. Parkinson’s Disease, March of Dimes) will be disseminated by the COEC through partnerships with stakeholders such as the NJ Work Environment Council and the Occupational Training and Education Consortium, and the NJ American Parkinson Disease Association Chapter.

Use of Center Facility Cores

The Center’s Facility Cores are key to the success of the Neurological Disease Core. The IHFSC is central to the NIEHS funded translational study investigating the combined effects of lead and stress among lead-exposed painters (N. Fiedler). Investigators documented neuronal loss and characterized the progression of neuronal injury following exposure to the dithiocarbamate pesticide, maneb, through the Biological Response Indicators Core.  The Chemical Analysis Core developed methods that permitted identification of the toxicant and metabolites in the intact cell or tissue, and for the first time showed that paraquat persisted unmetabolized in neuronal cells.

R. Zhou and K. Reuhl study the interplay between adhesion and repulsion molecules and metal neurotoxicants using the Biological Response Indicators Facility Core to localize and measure specific molecules within the brain.  This work led to studies of these molecules as mediators of learning and memory involving G. Wagner and E. DiCicco-Bloom. This initiative has expanded to translational assessment of neural injury response indicators through collaborations with O. Mirochnitchenko, and to chemical prevention studies in collaboration with C.S. Yang.  The Center pilot project program has played an essential role in attracting new clinical collaborators (e.g., L. Golbe, M. Lewis, and T. Rugino) and supporting innovative approaches of newly recruited Core faculty (J. Richardson and M. Thiruchelvam).