The goals of this proposal are to 1) define mechanisms used by the TSC genes to control the generation of neurons and then glia from neural progenitor cells and 2) determine how defects in these processes result in cortical malformations in Tuberous Sclerosis Complex (TSC). TSC is caused by mutation of either the TSC1 or TSC2 genes and is the most common genetic cause of epilepsy and autism. These features are very likely due to cortical brain malformations (tubers) that are found in almost all patients. Previous work has demonstrated severe laminar disruptions within tubers with abnormal glia, dysmorphic neurons, and """"""""giant"""""""" cells expressing neuronal as well as glia markers. These findings suggest that the TSC genes play a critical role during the generation of specific neuronal populations as well as the switch from neuronal to glia production by neural progenitor cells. Mechanisms that normally control this process are not well understood but appear linked to cell cycle exit and the length of G1. Proliferation, total cell cycle length, and G1 duration are mediated by cyclins, cyclin-dependent kinases (cdk), and cdk inhibitors such as p27kip1 (p27). Notably, while Tsc1 or Tsc2-deficient fibroblasts have decreased levels and activity of p27, similar alterations in Tsc1 or Tsc2-deficient neural progenitor cells have not been reported.
Our Specific Aims are: 1) Determine the role of the Tsd gene on the timing of neuronal and glia production from neural progenitor cells, 2) determine G1 duration and proliferation in 7sc1-deficient neural progenitor cells, and 3) determine p27 expression, subcellular localization, and function in 7sc7-deficient neural progenitor cells. We will achieve these aims by studying 7sc1-deficient neural progenitor cells both in vivo and in vitro. The ability of these neural progenitor cells to differentiate will be determined using lineage specific markers. In addition, we will use S phase tracers to measure cell cycle length, G1 duration, and the proportion of cells that are actively proliferating in mice with Tsc1-deficient neural progenitor cells. Finally, p27 expression, subcellular localization, and function will be determined. The candidate will utilize this K08 Award to gain expertise in developmental neurobiology though interactions with his mentor, the Neuroscience research community at Vanderbilt University, and active involvement with national and international leaders in Developmental Neurobiology. Overall, this award should position him to become an independent physician-scientist who will successfully compete for future extramural NIH funding. Relevance: Tuberous Sclerosis Complex (TSC) is a genetic disease whose manifestations include seizure disorders, brain tumors, autism and developmental delay. This proposal seeks to understand the role of abnormal neural progenitor cells to TSC. These findings will likely have broad therapeutic implications for individuals with TSC as well as non-TSC patients with seizure disorders and autism. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS050484-02
Application #
7448681
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2007-06-15
Project End
2012-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$165,629
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
West, Kathryn L; Kelm, Nathaniel D; Carson, Robert P et al. (2018) Myelin volume fraction imaging with MRI. Neuroimage 182:511-521
West, Kathryn L; Kelm, Nathaniel D; Carson, Robert P et al. (2018) Experimental studies of g-ratio MRI in ex vivo mouse brain. Neuroimage 167:366-371
Kelm, Nathaniel D; West, Kathryn L; Carson, Robert P et al. (2016) Evaluation of diffusion kurtosis imaging in ex vivo hypomyelinated mouse brains. Neuroimage 124:612-626
Grier, Mark D; Carson, Robert P; Lagrange, Andre Hollis (2015) Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells. PLoS One 10:e0124649
Grier, Mark D; Carson, Robert P; Lagrange, Andre H (2015) Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman syndrome are dependent on maternal and dietary influences. Behav Brain Res 291:260-267
Carson, Robert P; Fu, Cary; Winzenburger, Peggy et al. (2013) Deletion of Rictor in neural progenitor cells reveals contributions of mTORC2 signaling to tuberous sclerosis complex. Hum Mol Genet 22:140-52
Armour, Eric A; Carson, Robert P; Ess, Kevin C (2012) Cystogenesis and elongated primary cilia in Tsc1-deficient distal convoluted tubules. Am J Physiol Renal Physiol 303:F584-92
Fu, Cary; Cawthon, Bryan; Clinkscales, William et al. (2012) GABAergic interneuron development and function is modulated by the Tsc1 gene. Cereb Cortex 22:2111-9
Carson, Robert P; Van Nielen, Dominic L; Winzenburger, Peggy A et al. (2012) Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin. Neurobiol Dis 45:369-80
Ess, Kevin C (2010) Tuberous sclerosis complex: a brave new world? Curr Opin Neurol 23:189-93

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