Bio

Bio


Kristy did her undergraduate work at Bates College in Lewiston, ME where she received a BA in Biology in 2012. She then moved to Athens, GA where she obtained a PhD in Pharmaceutical and Biomedical Sciences from the University of Georgia in 2017. Her research investigated the role of the transcription factor HIF-1a in thiamine (vitamin B1) deficiency-induced neurological damage. She joined the Buckwalter lab in late 2017 to continue researching mechanisms of neurodegeneration and neuroinflammation. She is interested in investigating the role of astrocytes in neuroinflammation following stroke. Ultimately, understanding how astrocytes mediate neuroinflammation in the context of disease and neurological injury may identify therapeutic targets to protect the brain following injury.

Honors & Awards


  • Outstanding Teaching Assistant, University of Georgia Graduate School (2017)

Boards, Advisory Committees, Professional Organizations


  • Member, American Association of Pharmaceutical Scientists (2013 - Present)
  • Member, Sigma Xi (2012 - Present)

Professional Education


  • Bachelor of Arts, Bates College (2012)
  • Doctor of Philosophy, University of Georgia (2017)

Research & Scholarship

Lab Affiliations


Publications

All Publications


  • The Local and Peripheral Immune Responses to Stroke: Implications for Therapeutic Development. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Zera, K. A., Buckwalter, M. S. 2020

    Abstract

    The immune response to stroke is an exciting target for future stroke therapies. Stroke is a leading cause of morbidity and mortality worldwide, and clot removal (mechanical or pharmacological) to achieve tissue reperfusion is the only therapy currently approved for patient use. Due to a short therapeutic window and incomplete effectiveness, however, many patients are left with infarcted tissue that stimulates inflammation. Although this is critical to promote repair, it can also damage surrounding healthy brain tissue. In addition, acute immunodepression and subsequent infections are common and are associated with worse patient outcomes. Thus, the acute immune response is a major focus of researchers attempting to identify ways to amplify its benefits and suppress its negative effects to improve short-term recovery of patients. Here we review what is known about this powerful process. This includes the role of brain resident cells such as microglia, peripherally activated cells such as macrophages and neutrophils, and activated endothelium. The role of systemic immune activation and subsequent immunodepression in the days after stroke is also discussed, as is the chronic immune responses and its effects on cognitive function. The biphasic role of inflammation, as well as complex timelines of cell production, differentiation, and trafficking, suggests that the relationship between the acute and chronic phases of stroke recovery is complex. Gaining a more complete understanding of this intricate process by which inflammation is initiated, propagated, and terminated may potentially lead to therapeutics that can treat a larger population of stroke patients than what is currently available. The immune response plays a critical role in patient recovery in both the acute and chronic phases after stroke. In patients, the immune response can be beneficial by promoting repair and recovery, and also detrimental by propagating a pro-inflammatory microenvironment. Thus, it is critical to understand the mechanisms of immune activation following stroke in order to successfully design therapeutics.

    View details for DOI 10.1007/s13311-020-00844-3

    View details for PubMedID 32193840

  • Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1 NATURE MEDICINE Yousef, H., Czupalla, C. J., Lee, D., Chen, M. B., Burke, A. N., Zera, K. A., Zandstra, J., Berber, E., Lehallier, B., Mathur, V., Nair, R. V., Bonanno, L. N., Yang, A. C., Peterson, T., Hadeiba, H., Merkel, T., Koerbelin, J., Schwaninger, M., Buckwalter, M. S., Quake, S. R., Butcher, E. C., Wyss-Coray, T. 2019; 25 (6): 988-+
  • Stabilization of the hypoxia-inducible transcription Factor-1 alpha (HIF-1 alpha) in thiamine deficiency is mediated by pyruvate accumulation TOXICOLOGY AND APPLIED PHARMACOLOGY Zera, K., Zastre, J. 2018; 355: 180–88

    Abstract

    Vitamin B1, or thiamine is a critical enzyme cofactor required for metabolic function and energy production. Thiamine deficiency (TD) is common in various diseases, and results in severe neurological complications due to diminished mitochondrial function, oxidative stress, excitotoxicity and inflammation. These pathological sequelae result in apoptotic cell death in both neurons and astrocytes in distinct regions, in particular the thalamus and mammillary bodies. Comparable histological injuries in patients with hypoxia/ischemia (H/I) have also been described, suggesting a congruency between the cellular responses to these stresses. Analogous to H/I, TD stabilizes and activates Hypoxia Inducible Factor-1α (HIF-1α) even without changes in physiological oxygen levels. However, the mechanism of HIF-1α stabilization in TD is currently unknown. Using a pyruvate assay, we have demonstrated that TD induces pyruvate accumulation in mouse primary astrocytes which correlates to an increase in HIF-1α expression. Additionally, we utilized an enzymatic assay for pyruvate dehydrogenase to demonstrate a reduction in catalytic activity during TD due to lack of available thiamine pyrophosphate cofactor, resulting in the observed pyruvate accumulation. Finally, a pyruvate kinase inhibitor which limited pyruvate accumulation was utilized to demonstrate the role of pyruvate accumulation in HIF-1α stabilization during TD. These results reveal that stabilization of HIF-1α protein in TD centralizes on pyruvate accumulation in mouse primary astrocytes due to metabolic disruption of PDH.

    View details for DOI 10.1016/j.taap.2018.07.004

    View details for Web of Science ID 000442193300019

    View details for PubMedID 30008376

  • Thiamine deficiency activates hypoxia inducible factor-1 alpha to facilitate pro-apoptotic responses in mouse primary astrocytes PLOS ONE Zera, K., Zastre, J. 2017; 12 (10): e0186707

    Abstract

    Thiamine is an essential enzyme cofactor required for proper metabolic function and maintenance of metabolism and energy production in the brain. In developed countries, thiamine deficiency (TD) is most often manifested following chronic alcohol consumption leading to impaired mitochondrial function, oxidative stress, inflammation and excitotoxicity. These biochemical lesions result in apoptotic cell death in both neurons and astrocytes. Comparable histological injuries in patients with hypoxia/ischemia and TD have been described in the thalamus and mammillary bodies, suggesting a congruency between the cellular responses to these stresses. Consistent with hypoxia/ischemia, TD stabilizes and activates Hypoxia Inducible Factor-1α (HIF-1α) under physiological oxygen levels. However, the role of TD-induced HIF-1α in neurological injury is currently unknown. Using Western blot analysis and RT-PCR, we have demonstrated that TD induces HIF-1α expression and activity in primary mouse astrocytes. We observed a time-dependent increase in mRNA and protein expression of the pro-apoptotic and pro-inflammatory HIF-1α target genes MCP1, BNIP3, Nix and Noxa during TD. We also observed apoptotic cell death in TD as demonstrated by PI/Annexin V staining, TUNEL assay, and Cell Death ELISA. Pharmacological inhibition of HIF-1α activity using YC1 and thiamine repletion both reduced expression of pro-apoptotic HIF-1α target genes and apoptotic cell death in TD. These results demonstrate that induction of HIF-1α mediated transcriptional up-regulation of pro-apoptotic/inflammatory signaling contributes to astrocyte cell death during thiamine deficiency.

    View details for DOI 10.1371/journal.pone.0186707

    View details for Web of Science ID 000413168100090

    View details for PubMedID 29045486

    View details for PubMedCentralID PMC5646851

  • Role of HIF-1 alpha in the hypoxia inducible expression of the thiamine transporter, SLC19A3 GENE Zera, K., Sweet, R., Zastre, J. 2016; 595 (2): 212–20

    Abstract

    Ensuring continuous intracellular supply of thiamine is essential to maintain metabolism. Cellular homeostasis requires the function of the membrane bound thiamine transporters THTR1 and THTR2. In the absence of increased dietary intake of thiamine, varying intracellular levels to meet metabolic demands during pathophysiological stressors, such as hypoxia, requires adaptive regulatory mechanisms to increase thiamine transport capacity. Previous work has established the up-regulation of SLC19A3 (THTR2) gene expression and activity during hypoxic stress through the activity of the hypoxia inducible transcription factor 1 alpha (HIF-1α). However, it is unknown whether HIF-1α acts directly or indirectly to trans-activate expression of SLC19A3. This work utilized the breast cancer cell line BT-474 treated with 1% O2 or a hypoxia chemical mimetic deferoxamine to determine the minimal promoter region of SLC19A3 responsible for hypoxia responsiveness. In silico sequence analysis determined two contiguous hypoxia responsive elements in close proximity to the transcriptional start site of the SLC19A3 gene. Using a HIF-1α transcriptional factor ELISA assay, HIF-1α was capable of binding to a dsDNA construct of the SLC19A3 minimal promoter. Chromatin immunoprecipitation assay established that SP1 was bound to the SLC19A3 minimal promoter region under normoxic conditions. However, HIF-1α binding to the minimal promoter region occurred during hypoxic treatments, while no SP1 binding was observed under these conditions. This work demonstrates the direct binding and activation of SLC19A3 expression by HIF-1α during hypoxic stress, suggesting an important adaptive regulatory role for HIF-1α in maintaining thiamine homeostasis.

    View details for DOI 10.1016/j.gene.2016.10.013

    View details for Web of Science ID 000388778500012

    View details for PubMedID 27743994

    View details for PubMedCentralID PMC5097002

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