Overview: I am nominating myself for a NIH Director?s Pioneer Award, which if awarded, I would use to investigate homology-dependent epigenetic mechanisms of gene regulation in animal models and eventually humans. One aspect of my research has been to study a phenomenon called paramutation, which was discovered in plants and involves allele communication that leads to a mitotically and meiotically heritable change in gene expression. My hypothesis is that the paradigm-shifting mechanisms of allele communication, which we have uncovered operating in plant chromatin, also exists in mammals and could explain the aberrant segregation of certain ?genetic? diseases. I have organized this essay in 3 sections. In Background and Significance, I define epigenetics, briefly summarize the fields? current understanding of mechanisms and discuss its importance for understanding a number of human diseases. In Prior and Current Work, I summarize our prior work on paramutation, using this as a basis for illustrating my approach to science providing evidence for why this nomination should be considered in the NDPA process. In New Research Direction, I briefly describe the new approaches I am proposing, explain how this builds on my past work, and discuss why the NDPA process provides a unique opportunity to pursue this work.
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