Research in the Lodish laboratory focuses on several important areas at the interface between molecular cell biology and medicine:
A. Red blood cell development. We are characterizing many novel genes that are important for terminal stages of erythropoiesis, including gene induction and repression, chromatin condensation, and enucleation. A major focus is identifying genes and extracellular signals that regulate the self- renewal, proliferation, and differentiation of early (BFU-E) erythroid progenitor cells; extracellular signals include activators of the glucocorticoid and PPARα receptors and oxygen. This work has led to the characterization of several molecules, including two that are FDA-approved drugs for other indications, that show great promise as therapeutics for bone marrow failure disorders and erythropoietin- resistant anemias. This research involves extensive computational analyses of large datasets of gene expression profiles and chromatin modifications generated from cells at different stages of human and mouse red cell development.
B. Red blood cells as vehicles for the introduction of novel therapeutics, immunomodulatory agents, and diagnostic imaging probes into the human body. Red cells have a lifespan of 120 days and contain no DNA; any genes introduced into red cell precursors will no longer be present in the enucleated red cells introduced into a recipient. A large DARPA- supported project, in collaboration with Prof. Hidde Ploegh, involves the generation in culture of both murine and human red blood cells that have on their surface monoclonal antibodies that inactivate a variety of toxic substances, or receptors that can bind and remove unwanted materials from the blood. Red cells that have on their surface any of several covalently linked foreign or proteins induce immune tolerance and T cell anergy rather than an immune reaction, offering promise for novel treatments of several autoimmune disorders.
C. Long non-coding RNAs (lncRNAs). We focus on identifying and characterizing lncRNAs involved in modulation of cell differentiation along specific lineages. We have generated catalogs of lineage- specific lnc RNAs that are essential for the differentiation and function of erythroid cells, as well as others essential for formation of white and/or brown adipose cells. We are identifying their mRNA and protein targets, and studying their roles and mechanisms during cell development and disease.
D. Adipocyte biology. We are identifying genes and proteins involved in development of insulin resistance and stress responses in adipose cells, including their responses to reactive oxygen species.
What ties all of these projects together is their focus on the basic cell and molecular biology of genes and proteins important for human physiology and disease.