Our research efforts focus on three projects: (1) regulation of apolipoprotein-E gene expression, (2) structure-activity relationships for apoE gene expression modulators, and (3) development of small molecule Wnt mimetics.
Apolipoprotein-E (apoE) genotype is the biggest risk-factor for Alzheimer’s disease (AD). ApoE genotype is also associated with age-related cognitive decline and atherosclerosis – two conditions that contribute to AD pathogenesis. We have recently identified that a member of the orphan nuclear receptor family can regulate apoE gene expression through the apoE promoter in H4 human neuroglioma cells. We are in the process of identifying the DNA sequences in the apoE promoter and characterizing the transcription factors that bind to these promoter elements. This line of research could discover possible connections between metabolic/environmental processes and AD, and identify new targets that can be regulated to modify apoE gene expression and possibly AD-relevant processes.
In collaboration with Dr. Jonathan Stoddard and Dr. Santanu Maitra (CSU-Fresno), we have developed two new classes of compounds that activate or inhibit apoE gene expression in a cell line specific manner. Our current focus is to develop more potent cell line specific modulators of apoE gene expression through traditional medicinal chemistry approaches. One of the future goals of this project is to determine the mechanism underlying the differential regulation of apoE gene expression in these cell lines in response to the apoE modulators.
Wnt is an extracellular signaling molecule that is critical for certain cell-fate decisions during development. The downstream effect of the canonical Wnt pathway is to increase beta-catenin levels in the cell. The Wnt pathway is also critical for maintenance of stem cells in a pluripotent state, and is constitutively active in certain cancers due to mutations in the intermediary proteins of this pathway. In collaboration with Dr. Jonathan Stoddard and Dr. Peter de Lijser, we have designed several compounds that promote beta-catenin accumulation. We have already identified a small molecule Wnt mimetic that can maintain mouse embryonic stem cells in a pluripotent state. We plan to further develop the pharmacophores to yield drugs with higher potency. These Wnt mimetics are of value to stem cell maintenance, cancer research, and developmental biology.
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Wong AM, Patel NV, Patel NK, Wei M, Morgan TE, de Beer MC, de Villiers WJ, Finch CE. (2005) Macrosialin increases during normal brain aging are attenuated by caloric restriction. Neuroscience Letters 2005 390 76-80