The study of neurogenetic disorders like Angelman, Rett and fragile X syndromes as well as autism spectrum disorders has depended largely on the analysis of gene/protein expression in non-neuronal biospecimens like lymphoblast and fibroblast cel lines. Although some analysis has been possible in post-mortem human brain tissue for neurogenetic syndromes, this tissue is often of variable quality and in limited amounts. Recently there has been an initiative to induce pluripotent stem cels (iPSCs) from patient fibroblasts and differentiate these iPSCs into various neuronal lineages. There are several problems with this approach: 1) fibroblasts must be obtained though a fairly invasive skin biopsy which leaves a scar and causes undue pain and distress in developmentally disabled or autistic children;3) induction of fibroblasts into stem cells (reprogramming) and then into neuronal lineages is a laborious task that may not maintain epigenetic marks on the DNA that are essential to proper gene regulation in the native neuronal tissues;and 4) viral vectors which are themselves immunogenic are used to reprogram iPSCs limiting the downstream aplication of these neurons for therapeutic transplantations. Here we propose to use dental pulps from exfoliated primary teeth (EPT), as a source of stem cells for the study of a variety of neurogenetic syndromes. Dental pulp stem cells differentiate into functional neurons in vitro and in vivo. Dental pulps from EPT are also an easily obtainable source of cranial neural crest (CNC) cells. The majority of the cells in the peripheral nervous system, including neurons, are derived from the neural crest. Based on the extensive collaborative sum of our expertise in genetics, dental pulp stem cells and neurophysiology, we feel that this novel approach will provide a fresh perspective to the way we study expresion changes, epigenetics and neurophysiology in an ex-vivo model system for human neurogenetic disorders. !

Public Health Relevance

The primary goal of this proposal is to develop a method to investigate the neurons of patients with neurogenetic disease that uses shed teeth (primary teeth or puled teeth). If we can determine that tooth samples provide the right type of cells in the dental pulp to make neurons in culture we will have a new way to look at the gene expression and physiology of these patient-derived neurons. Having these cultures could lead to new insights into the mechanisms of human neurogenetic disease and even normal neuronal development and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS075709-02
Application #
8413042
Study Section
Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
Mamounas, Laura
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$217,125
Indirect Cost
$72,375
Name
University of Tennessee Health Science Center
Department
Neurology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163