The Heat shock Factor 1 (HSF-1) is a transcription factor that upon activation enters the nucleus and regulates the transcription of its target gene networks. In the nematode C. elegans, HSF-1 is critical for the regulation of a variety of fundamental biological functions including development and stress resistance. In addition, it mediates protection from toxic protein aggregation and longevity facilitated by reduction of the Insulin/IGF signaling pathway, functions that point to HSF-1 as a promising target for the development of neurodegeneration therapies. Despite its key regulatory importance and therapeutic potential, little is known about the gene netwroks regulated by HSF-1 and its co-factors. Here I propose a systematic study designed to explore the different aspects of HSF-1 roles in regulating longevity and countering toxic protein aggregation. First the timing in which HSF-1 regulates longevity and counter toxicity associated with the aggregation of the Alzheimer’s disease linked peptide, Aβ. Next, the relations with components of the Insulin/IGF signaling pathway and its target genes networks will be studied at the correct temporal pattern, followed by exploration of the molecular co-factors that interact with HSF-1 at the longevity assurance time window. The proposed study will shed light on the molecular mechanisms that prevent late onset neurodegenerative disorders to emerge early in life and will point to new avenues towards the development of novel neurodegeneration therapies.
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