Creatine Transporter Deficiency (CTD) is a metabolic disorder that occurs as a result of a mutation in the SLC6A8 gene which blocks the uptake of creatine (Cr) into the brain. This disrupts the buffering function of the phosphocreatine/creatine shuttle, which plays a key role in the regeneration of ATP. Without this shuttle, ATP homeostasis becomes dysregulated and proper cellular functions cannot be carried out, leading to a decline in cognition. Attempts at treating this disorder include supplementing with analogs of Cr or biosynthetic precursors of Cr. This has not proven to be a successful treatment option, as cerebral Cr levels remain low and cognition is not improved. The goal of our research is to better understand the effect of CTD on cellular bioenergetics, in order to aid in the development of effective therapies that ameliorate cognitive impairments. Our lab has generated a Crt knockout mouse (Crt -/y) that mirrors the symptomology of CTD patients and is therefore a useful tool for studying this metabolic disorder. We hypothesize that sustained activation of an alternate energy source, ketosis, via intake of the ketogenic diet (KD), will replenish ATP such that cellular functions are restored resulting in improved cognition. This approach would address cellular bioenergetics deficits by alternatively restoring ATP homeostasis independent of cerebral Cr transport and uptake. The central hypothesis for this study is that a KD is sufficient to ameliorate the cognitive and metabolic deficits seen in Crt -/y mice.
Aim 1 will assess the effect of ketosis on the metabolic function in Crt -/y mice, while Aim 2 will determine the impact the ketosis has on cognitive function in Crt -/ymice. Taken together, the data from these aims will provide the foundation for effectual therapeutic options for CTD.

Public Health Relevance

Intellectual disability is a well-established, hallmark symptom of Creatine Transporter Deficiency (CTD). However, the pathology of this life altering symptom is poorly understood. The proposed study will directly address this issue by assessing the metabolic and cognitive effects nutritional ketosis has on a mouse model of CTD. Activation of this alternative energy source could contribute to a clinically relevant approach to treating this disease, ultimately improving the quality of life for CTD patients.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31HD092224-01A1
Application #
9470294
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Krotoski, Danuta
Project Start
2018-09-24
Project End
2020-09-21
Budget Start
2018-09-24
Budget End
2019-09-23
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221