Much of Rao’s early research career at Harvard was focused on nuclear factor of activated T cells transcription factors and characterizing NFATs. Her lab found NFAT proteins, expressed by most immune cells, to play a role in the transcription of genes important to an immune response. They also had success in characterizing the diversity of NFAT proteins and their interactions with other transcription factors and immune proteins. Also while at Harvard, Rao contributed to the work of colleagues in research regarding the role of NFAT proteins related to activating calcium release-activated calcium channels in immune responses. Their lab found that immunodeficiency was the result of a mutation in the gene encoding CRAC channels, Orai1. This was due to the role calcium activation plays in the translocation of the NFAT proteins to the nucleus for transcription in the genome, and therefore proper immunity. Some of the more recent research Rao has been involved with at the La Jolla Institute for Immunology revolves around signaling pathways and their effect on gene expression related to immune cells and using immune cells as a model for this expression. Her lab focuses on the ten-eleven translocation proteins and their effect on cancer progression and cell lineage specification. TET proteins are demethylation proteins that alter gene expression by changing the methyl groups on the DNA nucleotide cysteine. Her lab at La Jolla displayed TET proteins' importance in proper embryonic cell gene expression and their role in cancer development, particularly in myeloid and hematological malignancies. They also outline the potential for TET proteins as targeted epigenetic therapy for these hematological malignancies. This focus also includes her consultation on work regarding T cell exhaustion. She and her colleagues worked to define the term T cell exhaustion as it is a term vaguely used to mean over stimulation of T cells by antigens. Further investigation with the help of many experts, help to better define the term depending on the source of antigens, either viral or tumor, and ranging from complete deficiency of function to simple loss or change in function of the T cells. They also speak to the difference of TCF1+ and TCF1−, and the differences in exhaustion due to specific cell type. Continuing with her work on T cell exhaustion, Rao is involved in research specifically focusing on the T cells found within tumors. She and her colleagues discovered T cells with chimeric antigen receptors become particularly exhausted when found residing in a tumor. They concluded that the Tox and Nr4a transcription factors play an important role in the exhaustion of T cells, and inhibition or disruption of these transcription factors could be a hopeful method for cancer immunotherapy.
