Sandra Zinkel
Assistant Professor of Medicine
Last active: 3/26/2019

Profile

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

 

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice. Wagner PN, Shi Q, Salisbury-Ruf CT, Zou J, Savona MR, Fedoriw Y, Zinkel SS (2019) Blood 133(2): 107-120
    › Primary publication · 30413413 (PubMed) · PMC6328629 (PubMed Central)
  2. Bid maintains mitochondrial cristae structure and function and protects against cardiac disease in an integrative genomics study. Salisbury-Ruf CT, Bertram CC, Vergeade A, Lark DS, Shi Q, Heberling ML, Fortune NL, Okoye GD, Jerome WG, Wells QS, Fessel J, Moslehi J, Chen H, Roberts LJ, Boutaud O, Gamazon ER, Zinkel SS (2018) Elife
    › Primary publication · 30281024 (PubMed) · PMC6234033 (PubMed Central)
  3. Cardiolipin fatty acid remodeling regulates mitochondrial function by modifying the electron entry point in the respiratory chain. Vergeade A, Bertram CC, Bikineyeva AT, Zackert WE, Zinkel SS, May JM, Dikalov SI, Roberts LJ, Boutaud O (2016) Mitochondrion : 88-95
    › Primary publication · 27085476 (PubMed) · PMC4860904 (PubMed Central)
  4. Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research. Zhou T, Kinney MC, Scott LM, Zinkel SS, Rebel VI (2015) Blood 126(9): 1057-68
    › Primary publication · 26077396 (PubMed) · PMC4551359 (PubMed Central)
  5. In aged mice, low surrogate light chain promotes pro-B-cell apoptotic resistance, compromises the PreBCR checkpoint, and favors generation of autoreactive, phosphorylcholine-specific B cells. Ratliff M, Alter S, McAvoy K, Frasca D, Wright JA, Zinkel SS, Khan WN, Blomberg BB, Riley RL (2015) Aging Cell 14(3): 382-90
    › Primary publication · 25727904 (PubMed) · PMC4406667 (PubMed Central)
  6. The loss of the BH3-only Bcl-2 family member Bid delays T-cell leukemogenesis in Atm-/- mice. Biswas S, Shi Q, Wernick A, Aiello A, Zinkel SS (2013) Cell Death Differ 20(7): 869-77
    › Primary publication · 23470523 (PubMed) · PMC3679453 (PubMed Central)
  7. Rejuvenating Bi(d)ology. Zinkel SS, Yin XM, Gross A (2013) Oncogene 32(27): 3213-3219
    › Primary publication · 23069655 (PubMed) · PMC4037911 (PubMed Central)
  8. MTG16 contributes to colonic epithelial integrity in experimental colitis. Williams CS, Bradley AM, Chaturvedi R, Singh K, Piazuelo MB, Chen X, McDonough EM, Schwartz DA, Brown CT, Allaman MM, Coburn LA, Horst SN, Beaulieu DB, Choksi YA, Washington MK, Williams AD, Fisher MA, Zinkel SS, Peek RM, Wilson KT, Hiebert SW (2013) Gut 62(10): 1446-55
    › Primary publication · 22833394 (PubMed) · PMC3663894 (PubMed Central)
  9. Acetaminophen inhibits cytochrome c redox cycling induced lipid peroxidation. Yin H, Vergeade A, Shi Q, Zackert WE, Gruenberg KC, Bokiej M, Amin T, Ying W, Masterson TS, Zinkel SS, Oates JA, Boutaud O, Roberts LJ (2012) Biochem Biophys Res Commun 423(2): 224-8
    › Primary publication · 22634010 (PubMed) · PMC3389218 (PubMed Central)
  10. Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress. Liu Y, Aiello A, Zinkel SS (2012) Cell Death Differ 19(10): 1602-12
    › Primary publication · 22522598 (PubMed) · PMC3438491 (PubMed Central)
  11. BID binds to replication protein A and stimulates ATR function following replicative stress. Liu Y, Vaithiyalingam S, Shi Q, Chazin WJ, Zinkel SS (2011) Mol Cell Biol 31(21): 4298-309
    › Primary publication · 21859891 (PubMed) · PMC3209332 (PubMed Central)
  12. Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress. Liu Y, Bertram CC, Shi Q, Zinkel SS (2011) Cell Death Differ 18(5): 841-52
    › Primary publication · 21113148 (PubMed) · PMC3074003 (PubMed Central)
  13. A role for proapoptotic Bax and Bak in T-cell differentiation and transformation. Biswas S, Shi Q, Matise L, Cleveland S, Dave U, Zinkel S (2010) Blood 116(24): 5237-46
    › Primary publication · 20813900 (PubMed) · PMC3012541 (PubMed Central)
  14. Bid regulates the pathogenesis of neurotropic reovirus. Danthi P, Pruijssers AJ, Berger AK, Holm GH, Zinkel SS, Dermody TS (2010) PLoS Pathog : e1000980
    › Primary publication · 20617182 (PubMed) · PMC2895667 (PubMed Central)
  15. Investigation of the proapoptotic BCL-2 family member bid on the crossroad of the DNA damage response and apoptosis. Zinkel SS (2008) Methods Enzymol : 231-50
    › Primary publication · 18662573 (PubMed)
  16. Bid plays a role in the DNA damage response. Zinkel SS, Hurov KE, Gross A (2007) Cell 130(1): 9-10; author reply 10-1
    › Primary publication · 17632047 (PubMed)
  17. BCL2 family in DNA damage and cell cycle control. Zinkel S, Gross A, Yang E (2006) Cell Death Differ 13(8): 1351-9
    › Primary publication · 16763616 (PubMed)
  18. A role for proapoptotic BID in the DNA-damage response. Zinkel SS, Hurov KE, Ong C, Abtahi FM, Gross A, Korsmeyer SJ (2005) Cell 122(4): 579-91
    › Primary publication · 16122425 (PubMed)
  19. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. Wang J, Iwasaki H, Krivtsov A, Febbo PG, Thorner AR, Ernst P, Anastasiadou E, Kutok JL, Kogan SC, Zinkel SS, Fisher JK, Hess JL, Golub TR, Armstrong SA, Akashi K, Korsmeyer SJ (2005) EMBO J 24(2): 368-81
    › Primary publication · 15635450 (PubMed) · PMC545811 (PubMed Central)
  20. Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Zinkel SS, Ong CC, Ferguson DO, Iwasaki H, Akashi K, Bronson RT, Kutok JL, Alt FW, Korsmeyer SJ (2003) Genes Dev 17(2): 229-39
    › Primary publication · 12533511 (PubMed) · PMC195974 (PubMed Central)
  21. Function of BID -- a molecule of the bcl-2 family -- in ischemic cell death in the brain. Plesnila N, Zinkel S, Amin-Hanjani S, Qiu J, Korsmeyer SJ, Moskowitz MA (2002) Eur Surg Res 34(1-2): 37-41
    › Primary publication · 11867899 (PubMed)
  22. BID mediates neuronal cell death after oxygen/ glucose deprivation and focal cerebral ischemia. Plesnila N, Zinkel S, Le DA, Amin-Hanjani S, Wu Y, Qiu J, Chiarugi A, Thomas SS, Kohane DS, Korsmeyer SJ, Moskowitz MA (2001) Proc Natl Acad Sci U S A 98(26): 15318-23
    › Primary publication · 11742085 (PubMed) · PMC65027 (PubMed Central)
  23. Death and survival signals determine active/inactive conformations of pro-apoptotic BAX, BAD, and BID molecules. Korsmeyer SJ, Gross A, Harada H, Zha J, Wang K, Yin XM, Wei M, Zinkel S (1999) Cold Spring Harb Symp Quant Biol : 343-50
    › Primary publication · 11232306 (PubMed)
  24. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA, Korsmeyer SJ (1999) Nature 400(6747): 886-91
    › Primary publication · 10476969 (PubMed)
  25. Transgenic studies with a keratin promoter-driven growth hormone transgene: prospects for gene therapy. Wang X, Zinkel S, Polonsky K, Fuchs E (1997) Proc Natl Acad Sci U S A 94(1): 219-26
    › Primary publication · 8990189 (PubMed) · PMC19291 (PubMed Central)
  26. Skin cancer and transgenic mice. Zinkel S, Fuchs E (1994) Semin Cancer Biol 5(1): 77-90
    › Primary publication · 8186391 (PubMed)
  27. DNA bend direction by phase sensitive detection. Zinkel SS, Crothers DM (1987) Nature 328(6126): 178-81
    › Primary publication · 3600796 (PubMed)
  28. Comparative gel electrophoresis measurement of the DNA bend angle induced by the catabolite activator protein. Zinkel SS, Crothers DM (1990) Biopolymers 29(1): 29-38
    › Primary publication · 2158360 (PubMed)
  29. c-mos expression in mouse oocytes is controlled by initiator-related sequences immediately downstream of the transcription initiation site. Pal SK, Zinkel SS, Kiessling AA, Cooper GM (1991) Mol Cell Biol 11(10): 5190-6
    › Primary publication · 1833632 (PubMed) · PMC361551 (PubMed Central)
  30. Catabolite activator protein-induced DNA bending in transcription initiation. Zinkel SS, Crothers DM (1991) J Mol Biol 219(2): 201-15
    › Primary publication · 1645410 (PubMed)
  31. Identification of a negative regulatory element that inhibits c-mos transcription in somatic cells. Zinkel SS, Pal SK, Szeberényi J, Cooper GM (1992) Mol Cell Biol 12(5): 2029-36
    › Primary publication · 1533271 (PubMed) · PMC364373 (PubMed Central)