Welcome to the Zinkel Lab

  • From left to right: Dr. Sandy Zinkel, MD, PhD (PI), Teresa Dugger (Senior research programs manager), Christi Salisbury-Ruf (Graduate student), Yuliya Hassan (RA II), and Dr. Jing Zou, MD, PhD (Post-doc)

  • Transmission electron microscopy (TEM) of human bone marrow aspirate from a normal control donor, an RCMD (refractory cytopenia with multilineage dysplasia), and RAEB (refractory anemia with excess blasts) patient. Increased necrosis is observed in both the RCMD and RAEB patients. Philips/FEI T-12 TEM, scale bar = 2m, 4,400X (Image credit: VU CISR, samples: Dr. Michael Savona

  • Bone marrow core tissue samples stained for RIPK1 (red) and the red cell marker CD71 (green), and nuclei with DAPI (blue). RIPK1 positive cells were correlated with CD71 positive cells in normal and MDS samples. Scale bar = 50 m (Image credit and staining: Dr. Jing Zou)

  • Confocal image of the bone marrow microenvironment of mouse models examining inflammation (TNFa; Cy5) and nucleated red blood cell precursors (Ter119; Alexa488). Red cell precursors cluster in groups, and can themselves be positive for or are adjacent to TNFa positive cells. Zeiss LSM 710, 63X (Image credit: Christi Salisbury-Ruf, staining: Teresa Dugger)

  • Our mitochondria project used an integrative approach, combining in vitro (cell culture) and in vivo (mouse models) observations with large-scale human genetics studies to reveal a novel role for the Bcl-2 protein Bid in the maintenance of mitochondrial cristae structure. We find a significant association between decreased BID expression and myocardial infarction (MI) as well as a coding SNP, M148T that decreased Bid’s interaction in the mitochondria with Mcl-1.

  • A Bid-/- mouse was challenged with an acute epinephrine stress and left ventricular heart tissue was fixed 18 hours later. Tissue was then examined for mitochondrial cristae structure and enlarged, misshaped cristae were observed corresponding to decreased mitochondrial and heart function. Philips/FEI T-12 TEM, 6,500X (Image credit: VU CISR)

  • Genetically determined gene expression (PrediXcan, Gamazon et al., 2015) can be used to identify a subgroup of patients in BioVU with the lowest 5% of BID – our closest model to a “Bid-/-“ people. These individuals have a greater than 4-fold increased risk for myocardial infarction (MI).

  • Blood 2019 133:107-120; doi

My lab is interested in understanding the mechanisms by which normal and malignant cells regulate programmed cell death. Multicellular organisms have devised a tightly regulated, genetically programmed mechanism of cell suicide to maintain homeostasis and to prevent propagation of genetically damaged cells. The discovery of the BCL-2 family of genes uncovered the underlying genetic mechanism of this regulation, as well as a class of oncogenes that governs cell death rather than cell proliferation.

There are two major pathways that regulation programmed cell death: apoptosis and programmed necrosis. Simply, apoptotic cells implode in a relatively immune silent manner. Necrotic cells explode, releasing cellular contents and inciting an immune response- beneficial in settings of infection, but detrimental in settings of chronic damage, where the inflammation elicited by necrotic cell death amplifies cellular damage. Current studies focus on how programmed cell death regulates homeostasis in the hematopoietic (blood) system. We have found that unrestrained programmed necrosis leads to bone marrow failure in mice that closely resembles the human disease Myelodysplastic syndrome (MDS), and find increased necrosis in human MDS bone marrow.

We are also interested in uncovering how genetically determined changes in expression of programmed cell death genes impacts susceptibility to human disease. We have utilized an integrative approach, leveraging mouse models as well as BioVU, to probe how genetically determined variations in gene expression can influence susceptibility to diseases such as myocardial infarction as well as bone marrow failure and leukemia.

The projects in my lab use hematopoietic cell culture systems, mouse models, immunofluorescence, electron microscopy, as well as flow cytometry and cell death assays to understand the signals and protein interactions that direct hematopoietic cells to die by apoptosis or necrosis. In addition, we use our mouse models to determine the effects of inhibiting necrosis on bone marrow failure and transformation to leukemia. Our studies provide new insights into the interplay between apoptosis and necrosis, and their role in hematopoiesis, bone marrow failure, and leukemogenesis. An additional focus is to determine the impact of genetically determined alterations in cell death pathways on susceptibility to human disease, using BioVU, in collaboration with Dr. Eric Gamazon