Programmed cell death is crucial for the development of multiple cell lineages and organs, as well as the maintenance of normal tissue homeostasis. Whereas pathologic cellular survival is seen in cancer and autoimmune diseases, excessive cellular demise is found in diseases such as neurodegeneration and myocardial infarction. The goal of the laboratory is to rigorously define and elucidate the cellular signaling network that dictates life and death in appropriate cellular contexts. This knowledge is basic to developing selective therapeutics.
A core focus of the laboratory is the expansive family of BCL-2 proteins. They comprise an intricate network of guardian and executioner proteins that govern the core pathway for programmed cell death in mammals. The role of the pro-apoptotic pore forming BCL-2 proteins in the development, maintenance and chemoresistance of malignancy is a fundamental molecular process studied by the laboratory
Of particular interest is a poorly understood family member called BOK, which is present in one of the 20 most frequently deleted genomic regions in all human cancers. Current evidence supports a role for BOK not only in the canonical apoptosis pathway, but in other cellular homeostasis pathways, such as the response to ER stress. How BCL-2 family members like BOK integrate these so-called "day-jobs" into their regulation of cell viability is of great interest. Using conditional mouse knockouts, biochemistry and genetic screening, we hope to unravel these complicated cellular signaling pathways. This knowledge will be important in devising therapeutic strategies to overcome blocks in apoptosis.
The immune system has an incredible capacity to selectively deliver cytotoxic strikes to defined targets. Understanding the determinants of both immune cell and cancer cell survival is important to optimize immunotherapy. Here we employ highly translational, synthetic engineering approaches to improve adoptive cellular therapy. Primary human T cells, Natural Killer (NK) cells and Tumor infiltrating lymphocytes (TILs) are reprogrammed using a multifactor mRNA approach developed by our collaborator, Sherman M. Weissman, Sterling Professor of Genetics. Our efforts are further strengthened by close collaborations with the Yale New Haven Hospital’s Advanced Cell Therapy core and several clinical oncologists.
Leukemia; Lymphoma; Stem Cells; Immunotherapy, Adoptive; Cell Death; Apoptosis; Genes, bcl-2; Mutant Chimeric Proteins; Endoplasmic Reticulum Stress; Cellular Reprogramming