Chozha V Rathinam

The overall goal of our research team is to delineate the molecular and biochemical bases of self-renewal of stem cells. In particular, we aim to understand how post-translational modifications of proteins regulate the "stemness" of stem cells. The major lines of our current investigation include: Decode the genetic basis of self-renewal of Hematopoietic Stem Cells: Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate into all lineages of the hematopoietic compartment. A constellation of intrinsic and extrinsic cellular mechanisms regulate self-renewal versus differentiation of HSCs. In the past few decades, significant progress has been made towards the understanding of cellular and molecular identities of HSCs. Nonetheless, the molecular machinery that controls the "stemness" of HSCs remains largely unknown. In an attempt to unravel the significance of post-translational modifications in the self-renewal, we identified the importance of 2 major families of E3 ubiquitin ligases; 1. RING finger family- c-Cbl and 2. HECT family-Itch in the self-renewal of HSCs. These studies have unequivocally proven the importance of ubiquitylation events and E3 ligases in the control of HSC development and functions. Of note, our approach of 'decoding self-renewal of stem cells through ubiquitylation' has been considered as a novel avenue of stem cell biology by the experts in the field (Yokomizo and Dzierzak, Genes and development, 2008). Even though our earlier studies have provided clues on the significance and physiological relevance of post-translation modifications in HSCs, still much work needs to be done in this area in order to understand the mechanisms and pathways through which self-renewal of HSCs is regulated. To this end, we are intensively investigating the importance and specificity of E3 ubiquitin ligases in the self-renewal process. Decipher aberrant molecular events that give rise to Leukemic Stem Cells: One of the major challenges in cancer biology is to define aberrant molecular pathways that cause transformation of normal stem cells to cancer stem cells. Pioneering studies over a decade have highlighted the phenotypic and functional similarities between normal stem cells and cancer stem cells. Growing evidence suggests that pathways that regulate the self-renewal of normal stem cells are deregulated in cancer stem cells resulting in the continuous expansion of self-renewing cancer cells and tumor formation. We recently documented that a deficiency in c-Cbl mediated ubiquitylation events results in the transformation of normal HSCs into Leukemic Stem Cells (LSCs). Strikingly, when we blocked signal transduction pathways mediated through the cytokine-Flt3L in HSCs, the onset of leukemia in c-Cbl mutant animals is prevented. In line with our observations, recent studies from several groups have reported that human cancers including MPD, AML and JMML are associated with frequent mutations in c-CBL. Overall,these observations highlight the importance of ubiquitylation events and underline the key functions of E3 ubiquitin ligases in the prevention of hematologic cancer. Currently, we are actively engaged in the identification of signal transduction pathways that contribute to the transformation of normal HSCs into LSCs. In addition, we focus on the importance of post-translational modifications of signal transducers in the phenomenon of Leukemic transformation. Unravel the molecular identities of Mesenchymal Stem Cells: Mesenchymal Stem Cells (MSCs) are multipotent stem cells that can differentiate into many lineages, including Osteoblasts, Chondrocytes, Myocytes and Adipocytes. MSCs also play a very important role in immune modulation through secretion of a variety of cytokines, growth factors and chemokines. Recently, MSCs and its progenies are shown to form and control the hematopoietic "niche" of the bone marrow. These properties make these specialized cells potentially ideal candidates for tissue engineering and cell based therapies. While MSCs hold a great promise as therapeutic agents in regenerative medicine, the cellular and molecular identities of MSCs are not well elucidated. In fact, only in the past few years the exact immunophenotype of murine MSCs has been described. In an effort to contribute to a better understanding of MSC biology, we are interested in uncovering both extrinsic and intrinsic control of MSC self-renewal and functions. We are currently looking for highly motivated students, and postdoctoral fellows.