Anjana Rao is a cellular and molecular biologist of Indian ethnicity, working in the US. She uses immune cells as well as other types of cells to understand intracellular signaling and gene expression. Her research focuses on how signaling pathways control gene expression.
Rao earned her master’s degree in physics from Osmania University in India, her Ph.D. in Biophysics from Harvard University, and completed a postdoctoral fellowship at the Dana-Farber Cancer Institute. [1] [2] She was a Professor of Pathology at Harvard Medical School until 2010, when she moved to be Professor at the La Jolla Institute for Immunology and Adjunct Professor in Pharmacology at the University of California San Diego. [1] With her collaborator Patrick Hogan (also Professor at the La Jolla Institute for Immunology), she is a cofounder of the company Calcimedica. [1] [2] She spent eight years on the Jane Coffin Childs Board of Scientific Advisors, a Foundation that supports cancer research, specifically research focusing on controlling the growth and development of cancer cells. [3] She is also a member of the Scientific Advisory Board of the Cancer Research Institute, a non-profit organization that supports scientific research on cancer immunotherapy, one of the most promising cancer treatments currently available. [4]
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Rao has been elected to the US National Academy of Sciences, the American Academy of Arts and Sciences, and the American Association for the Advancement of Science. She is a member of the American Association of Immunologists and the American Society for Biochemistry and Molecular Biology.
Rao’s early research at Harvard was focused on NFAT (Nuclear Factor of Activated T-cells) transcription factors, which she discovered with postdoctoral fellows Jugnu Jain and Pat McCaffrey and collaborator Patrick Hogan. [5] [6] They showed that NFAT proteins were expressed by most immune cells, and were essential for transcription of genes important for an immune response. [5] [6] They also showed that NFAT was regulated by calcium and the calcium-dependent phosphatase calcineurin, which removes phosphate groups from NFAT to allow it to enter into the nucleus of the cell, and that it partnered with the unrelated transcription factors Fos and Jun to turn on T cell activation. [5] [6]
Also while at Harvard, Rao, Hogan, and postdoctoral fellows Yousang Gwack and Stefan Feske, with colleagues Richard Lewis and Murali Prakriya at Stanford, discovered the molecular identity of Calcium Release-Activated Calcium (CRAC) channels which are necessary for calcium to enter most cells in the body. [7] [8] They discovered that an inherited immunodeficiency was caused by a mutation in the gene encoding the CRAC channel ORAI1. [7] The immunodeficiency was due to the role calcium activation plays in the translocation of NFAT proteins to the nucleus, which then turn on immune response genes including cytokine genes such as Interleukin-2. [9] In the immunodeficient patients, the mutation in ORAI1 caused a complete loss of calcium entry and left the children susceptible to different kinds of infections. [7]
Just before moving from Harvard to the west coast, Rao discovered the TET (Ten-Eleven Translocation) proteins with graduate student Mamta Tahiliani and collaborator Dr. L. Aravind. [10] They showed that all three TET proteins are enzymes that alter gene expression by oxidizing the methyl group of the “fifth base”, 5-hydroxymethylcytosine, and causing DNA demethylation, replacement of 5-methylcytosine by cytosine. [10] [11] At the La Jolla Institute, her lab demonstrated the importance of TET enzymes in proper gene expression, both in various cells of the immune system and during embryonic development. [12] They also highlighted the role of TET proteins in suppressing cancer development, particularly in lymphoid, myeloid and other hematological malignancies, [12] and outlined the potential for TET activators such as Vitamin C as targeted epigenetic therapy for these hematological malignancies. [13]
As a continuation of their longstanding interest in NFAT and calcium signalling, Rao and Hogan have also performed research on T cell exhaustion. [14] With colleagues, they worked to define the term T cell exhaustion, which was vaguely used to mean decreased immune responses due to overstimulation of T-cells by antigens. [15] Their research specifically focuses on T cells found within tumors. They and their colleagues have shown that like normal T cells, T cells with Chimeric Antigen Receptors (CAR) become exhausted when residing in a tumor. They concluded that TOX and NR4A transcription factors play an important role in the exhaustion of T cells, and that inhibition or disruption of these transcription factors is a promising approach for cancer immunotherapy. [16] [17]
T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.
In immunology, anergy is a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal immune response against a specific antigen, usually a self-antigen. Lymphocytes are said to be anergic when they fail to respond to their specific antigen. Anergy is one of three processes that induce tolerance, modifying the immune system to prevent self-destruction.
Calcium release-activated channels (CRAC) are specialized plasma membrane Ca2+ ion channels. When calcium ions (Ca2+) are depleted from the endoplasmic reticulum (a major store of Ca2+) of mammalian cells, the CRAC channel is activated to slowly replenish the level of calcium in the endoplasmic reticulum. The Ca2+ Release-activated Ca2+ (CRAC) Channel (CRAC-C) Family (TC# 1.A.52) is a member of the Cation Diffusion Facilitator (CDF) Superfamily. These proteins typically have between 4 and 6 transmembrane α-helical spanners (TMSs). The 4 TMS CRAC channels arose by loss of 2TMSs from 6TMS CDF carriers, an example of 'reverse' evolution'.
FOXP3, also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.
The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.
Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.
Calcium release-activated calcium channel protein 1 is a calcium selective ion channel that in humans is encoded by the ORAI1 gene. Orai channels play an important role in the activation of T-lymphocytes. The loss of function mutation of Orai1 causes severe combined immunodeficiency (SCID) in humans The mammalian orai family has two additional homologs, Orai2 and Orai3. Orai proteins share no homology with any other ion channel family of any other known proteins. They have 4 transmembrane domains and form hexamers.
Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the NFATC2 gene.
Nuclear factor of activated T-cells, cytoplasmic 1 is a protein that in humans is encoded by the NFATC1 gene.
Nuclear factor of activated T-cells 5, also known as NFAT5 and sometimes TonEBP, is a human gene that encodes a transcription factor that regulates the expression of genes involved in the osmotic stress.
Nuclear factor of activated T-cells, cytoplasmic 3 is a protein that in humans is encoded by the NFATC3 gene.
PR domain zinc finger protein 1, or B lymphocyte-induced maturation protein-1 (BLIMP-1), is a protein in humans encoded by the gene PRDM1 located on chromosome 6q21. BLIMP-1 is considered a 'master regulator' of hematopoietic stem cells, and plays a critical role in the development of plasma B cells, T cells, dendritic cells (DCs), macrophages, and osteoclasts. Pattern Recognition Receptors (PRRs) can activate BLIMP-1, both as a direct target and through downstream activation. BLIMP-1 is a transcription factor that triggers expression of many downstream signaling cascades. As a fine-tuned and contextual rheostat of the immune system, BLIMP-1 up- or down-regulates immune responses depending on the precise scenarios. BLIMP-1 is highly expressed in exhausted T-cells – clones of dysfunctional T-cells with diminished functions due to chronic immune response against cancer, viral infections, or organ transplant.
Nuclear factor of activated T-cells, cytoplasmic 4 is a protein that in humans is encoded by the NFATC4 gene.
Stromal interaction molecule 2 (STIM2) is a protein that in humans is encoded by the STIM2 gene.
Protein orai-2 is a protein that in humans is encoded by the ORAI2 gene.
Thymocyte selection-associated high mobility group box protein TOX is a protein that in humans is encoded by the TOX gene. TOX drives T-cell exhaustion and plays a role in innate lymphoid cell development.
Tet methylcytosine dioxygenase 2 (TET2) is a human gene. It resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies.
LiMETER stands for light-inducible membrane-tethered peripheral endoplasmic reticulum (ER). LiMETER is an optogenetics tool designed to reversibly label cortical ER or the apposition between plasma membrane (PM) and endoplasmic reticulum (ER) membranes.
Patrick G. Hogan is a cellular and molecular biologist who studies how cellular signaling leads to gene expression. He obtained his bachelor’s degree from Harvard University and a PhD in neurobiology from Harvard Medical School. In 2010, he moved to the La Jolla Institute for Immunology in San Diego as a Professor in the Division of Signaling and Gene Expression. He is a Founder and Member of the Scientific Advisory Board, CalciMedica Inc, La Jolla, CA.
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