Hamartin and tuberin, the protein products of TSC1 and TSC2 genes, form a functional complex which normally serves as an inhibitor in the mammalian target of rapamycin (mTOR) signaling pathway to prevent excessive growth and proliferation. Mutation of one of above-mentioned two genes will cause tuberous sclerosis complex (TSC). TSC is an autosomal dominant disease and characterized by benign tumor or hamartoma formation in multiple organs, such as the brain, skin, and kidneys. Most of individuals with TSC have brain lesions and exhibit neurological symptoms such as seizures, intellectual disability, learning disabilities, long-term and working memory deficits, and cognitive dysfunction. Although mTOR inhibitors such as sirolimus and everolimus were used in animal models or in patients and showed efficacy in the treatment of TSC related manifestations, treatment-related serious adverse events were reported. Curcumin is a polyphenol natural product of the plant Curcuma longa and is extremely safe and well tolerated, even at very high dose in humans. Recent studies revealed that curcumin was able to inhibit mTOR activity. Therefore, we assume that curcumin may represent a new class of mTOR inhibitor and used for TSC treatment. Our preliminary results showed that curcumin treatment can inhibit mTOR activity in vivo and rescue object recognition memory loss in the TSC2 knockout mouse, a TSC animal model. This knockout mouse also exhibits abnormal long term potentiation, which may lead to inappropriate information storage and consequently memory impairment. In addition, the neurological features of TSC including cognitive impairments may correlate to the microstructural abnormalities such as white matter abnormalities of the brain. By using electrophysiological and magnetic resonance imaging approaches, we also found that curcumin treatment can reverse the abnormal LTP and altered white matter microstructure. Our preliminary data suggest that curcumin is a potential therapeutic agent for TSC. In this proposal, we will further investigate the efficacy and mechanism of curcumin in the treatment of TSC related manifestations. The dosage effects of curcumin for ameliorating the neurological manifestations in TSC2 knockout mice will be further evaluated. Pathological analysis will be used to examine whether curcumin treatment could also improve non-neurological problems such as renal lesions. Hematological and biochemical parameters such as blood glucose level and red blood cell counts will be monitored during the treatment to evaluate possible side effects of long-term treatment with curcumin. Furthermore, possible mechanisms by which curcumin inhibit mTOR signaling will be examined. For example, protein expressions of mTOR and raptor will be examined by Western blot analysis. PP2A and AMPK activity will be measured by activity assay kits. The interaction of mTOR and raptor will be examined by immunoprecipitation. Results of the proposed studies will provide a new therapeutic agent for TSC.
|Effective start/end date||8/1/16 → 7/31/17|