2013 Research Grant

Controlling Cell Differentiation through Modular Assembly of Cell-permeable Transcription Regulating Proteins. 

Conducted by Dr. Rahul Palchaudhuri at Harvard University. Funded in Partnership with the Life Sciences Research Foundation.

Healthy blood cells follow an established life cycle, starting as stem cells, developing into blood cell progenitors, and then differentiating into specific types of cells. Properly differentiated cells mature and eventually die. In many cases of AML, however, the cells are genetically damaged so they never differentiate and mature, and instead proliferate out of control.

Dr. Palchaudhuri’s aim is to re-program the cellular processes of leukemic cells so that normal cell differentiation can once again occur, enabling blood cells to mature and die. He is targeting the abnormal activity of two “homeodomain proteins” which block the differentiation of myeloid cells, and plans to engineer “cell-permeable homeodomain fusion proteins” (HFPs) to stop the instructions that block differentiation. He will also use a novel technique called “hydrocarbon peptide stapling” to control the shape of the HFPs and enable them to enter the cell.

Dr. Palchaudhuri will first develop the HFPs and determine if they properly bind to their target, then test whether the HFPs induce AML cell differentiation in culture and in a mouse model. If successful, the approach would offer the promise of differentiation-inducing therapy for approximately 70% of AML patients. By overcoming current limitations in DNA-targeting technologies, it may be readily extended to other diseases as well.

   Dr. Palchaudhuri in the lab.