2015 — 2016 |
Skelton, Matthew R |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
The Role of Na+, K+-Atpase Function in Creatine Transporter Deficiency @ Cincinnati Childrens Hosp Med Ctr
? DESCRIPTION (provided by applicant): Disruptions in energy supply and utilization within the brain have severe functional consequences. In particular, the loss of the creatine (Cr)-phosphocreatine (PCr) shuttle leads to severe intellectual disability, epilepsy and aphasia. The Cr-PCr shuttle is responsible for rapid ATP replenishment. The most prevalent cause of Cr loss in the brain is due to mutations in the X-linked Cr transporter (CrT). To date, there are no treatments available for CrT deficiency. In order to better understand the pathophysiology of CrT deficiency as well as to develop and screen treatments, we generated CrT knockout (CrT-/y) mice that show severe cognitive deficits similar to CrT deficient patients. While Cr deficiency is the root of the cognitive disorders, it likely does not play a direct role in cognitive function. I is likely that the loss of Cr leads to larger disruptions of systems directly involved in neuronal function. It is essential to identify these systems and determine how the loss of Cr affects their function. Na+,K +-ATPases (NKA) are essential for proper cognitive function and consume 50-60% of the brain's resting metabolic output. Previous studies, along with preliminary data from our lab, show that Cr is essential for proper function of NKA. The mechanisms underlying the role of the Cr-PCr shuttle on NKA function has not been elucidated. The purpose of this proposal is to identify the mechanisms underlying the interaction between NKA and Cr. The hypothesis for this proposal is that the rapid ATP turnover provided by Cr-PCr shuttle is required for proper NKA activity. In aim 1, the role of each component of the Cr-PCr shuttle (Cr, PCr, ATP) on NKA function will be evaluated. The effects of a potential treatment for Cr deficiency, cyclocreatine, on NKA function will be determined as well. In aim 2, the effect of Cr-deficiency on the individual NKA catalytic subunits function will be evaluated. Each subunit has a unique function within the brain, making it essential to determine how the loss of Cr disrupts their function. Upon the completion of these studies, a direct link between the loss of Cr and NKA function will be established, shedding light onto the function of NKA, an essential protein for brain function as well as advancing the understanding of CrT deficiency, a significant human disorder.
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0.939 |
2019 |
Skelton, Matthew R |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Using a Ketogenic Diet to Treat Creatine Transporter Deficiency @ Cincinnati Childrens Hosp Med Ctr
Project Summary Creatine transporter deficiency (CTD) is a metabolic disorder that results in a lack of cerebral creatine (Cr). The primary phenotype of CTD is intellectual disability, aphasia, and epilepsy. There are no treatments available for CTD. In order to understand CTD, we have developed Creatine transporter knockout (Slc6a8-/y) mice that have significant cognitive deficits. The main function of Cr is to replenish ATP levels during times of high energy demand. Compared with Slc6a8+/y mice, Slc6a8-/y mice have reduced ATP levels along with increases in whole-body and cellular metabolism. This phenotype makes the Slc6a8-/y mouse an ideal model in which to test potential therapies. The long-term goal of this research is to develop safe and effective treatments for CTD. While the primary treatment options involve restoring Cr function, the possibility of alternative/adjunctive therapies should be explored. If the ATP deficits in Slc6a8-/y mice underlie the cognitive deficits, it stands to reason that increasing ATP levels should restore cognitive function. Ketone bodies (KB) are energetically favorable mitochondrial substrates, producing more ATP per molecule than glucose. Blood and brain KB can be elevated using a ketogenic diet, which is high in fat and low in carbohydrates. The KD increases ATP levels in other mouse models with brain ATP reductions. The hypothesis of this study is that a KD is sufficient to ameliorate the cognitive and metabolic deficits observed in Slc6a8-/y mice. In order to test this hypothesis, 2 specific aims have been devised. In specific aim 1, effects of a KD will be evaluated. The diet will be initiated in young mice in order to model early age treatment in humans. Following 6 weeks on the diet, spatial learning and memory, novel object recognition, and conditioned fear will be evaluated. Brain ATP levels will be measured following testing. In specific aim 2, a group of Slc6a8-/y mice will be treated with MCT oil to increase ketone body levels without the cardiovascular and growth-related concerns that often surround a KD. Neuronal morphology will be evaluated in both groups of mice. Taken together, these studies will provide a significant advancement in the treatment and understanding of CTD and the role of Cr in the brain.
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0.939 |