UCSF

Research and Projects

Our lab takes a chemical biology and proteomics approach to optimizing drug selectivity and studying the immune system and blood formation. Our research is divided into three main foci:

  1. Developing cell selective therapeutics through differential cellular metabolism
  2. Identifying proteins that regulate the innate immune system
  3. Elucidating the relationship between mRNA and protein in hematopoietic stem cells

1. Developing cell selective therapeutics through differential cellular metabolism

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Traditional drug development relies on the identification of targets that are not only required for survival, growth, and proliferation in malignant cells or pathogens but are also not expressed, or at least not required, for survival in healthy or host cells and tissues. Not surprisingly, this is a tall order. Our laboratory is identifying and exploiting differences in the expression and activity of enzymes associated with drug metabolism in order to develop covalent small molecule tools and therapeutics that can be efficiently metabolized, and therefore inactivated, in cell types we want to protect but are allowed to persist in their active covalent form in target cells.

2. Identifying proteins that regulate the innate immune system

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Innate immune checkpoint blockade is a therapeutic strategy beginning to demonstrate efficacy in the clinic. To date, four innate immune signaling axes have been identified, which, when blocked, promote macrophage-mediated phagocytosis, or “eating” of target cancer cells. These axes consist of a “don’t eat me” signal on the target cell and a complementary receptor on the macrophage. However, if we block all known “don’t eat me” signals, we still do not get complete clearance of target cells. This suggests there are more of these signaling axes to discover. Our lab is interested in taking a mass spectrometry or proteomics approach to identify proteins uniquely expressed by phagocytic macrophages (“eaters”), non-phagocytic macrophages (“non-eaters”) as well as uneaten target cells and bacteria. These studies will enable us to interrogate this process from both sides of the signaling axis in a single experimental workflow.

3. Elucidating the relationship between mRNA and protein in hematopoietic stem cells

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Hematopoietic stem cells (HSCs) are responsible for generating our blood supply throughout life. They can either choose to self-renew into daughter HSCs or to differentiate into progenitors in response to physiological demands. As we age, and in hematologic malignancies, blood formation can become dramatically misregulated. Historically, protein expression in aged and adult HSCs was not well understood. However, we recently reported mass spectrometry-based protein characterization of aged and adult HSCs and their progenitors, and we compared our findings to RNA-sequencing data for these cell types. These studies revealed a unique relationship between mRNA and protein in the HSC compartment. Although HSCs display higher levels of message diversity and more open chromatin, they have reduced levels of protein diversity and lower rates of translation. Our lab is following these findings to understand this unique relationship and to investigate how it changes during aging and disease.