Dr. Francisco Cayabyab PhD

Dr. Cayabyab’s work focuses on adenosine receptor signaling in brain diseases, and the biology of breast cancer and brain cancer. Interests: stroke; Parkinson's disease; epilepsy; neurophysiology; confocal imaging; biochemistry.

Our research aims to find new therapies in stroke, epilepsy, Parkinson's disease (PD), and brain cancer. We use a multi-disciplinary approach to understand the contribution of adenosinergic signaling in stroke and PD, the roles of ion channels in epileptogenesis, and signaling pathways involved in cancer progression. We also study roles of intruding immune cells in stroke and PD progression, using behavioral tests, electrophysiology, biochemistry, confocal imaging, and stroke and PD rat models.

ResearchGate

Academic Credentials:

• Postdoctoral Fellow, Brain Research Centre, Department of Psychiatry, University of British Columbia, 2004-2007.
• Postdoctoral Fellow, Cardiac Ion Channel Lab, School of Kinesiology, Simon Fraser University, 2002-2004.
• PhD. Degree, 2002, University of Toronto, Toronto, Ontario.
• M. Eng. (Electrical & Computer Engineering), 1995, McMaster University. Hamilton, Ontario.
• B. Eng. (Engineering Physics), 1990, McMaster University. Hamilton, Ontario.

Academic Appointments:

• Professor, Department of Surgery, University of Saskatchewan, July 2018 - present
• Associate Professor, Department of Surgery, University of Saskatchewan, July 2015-June 2018
• Associate Member, Department of Pharmacology, University of Saskatchewan, July 2015-present
• Assistant Professor, Department of Surgery, University of Saskatchewan, November 2014-June 2015
• Assistant Professor, Department of Physiology, University of Saskatchewan, February 2007-October 2014 (Tenured July 1, 2014)

Current Funding:

• The Heart and Stroke Foundation of Canada
• Saskatchewan Health Research Foundation (SHRF) Collaborative Innovation and Development Grant
• Natural Sciences and Engineering Research Council of Canada
• University of Saskatchewan College of Medicine

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Summary of Research Projects

A. Role of Adenosine Receptor Signaling in Stroke

It is widely believed that excessive levels of an excitatory brain chemical called glutamate during stroke is mostly responsible for the brain damage that progresses days and even weeks after the initial stroke injury. Another brain chemical called adenosine is also known to accumulate in diseased brains, and during a stroke the levels of adenosine can increase over 1000-fold. For years, scientists have identified both stimulatory and inhibitory actions of this endogenous brain chemical.  Because there appears to be a greater density of the inhibitory receptors for adenosine in the brain, it is widely believed that adenosine actions are mostly nerve-protective during stroke.  However, my lab has recently discovered that the so called inhibitory adenosine receptors contribute to brain damage and cognitive dysfunction in animal models of stroke.  In older brains, this adenosine-mediated nerve damage and cognitive deficit may be more pronounced as it is widely reported that aging brains have higher levels of adenosine.  We have uncovered a previously unknown mechanism for nerve damage in animal stroke models which may explain, in part, the higher risk for developing post stroke brain damage and dementia in stroke patients. We are further characterizing the intracellular molecular switches activated by adenosine receptors, and our goal is to target these switches to prevent brain damage and improve stroke outcomes.

B. Development of Stem Cell Therapy in a Novel Animal Model of Parkinson’s Disease

Parkinson's disease (PD) is characterized by loss of dopamine-producing neurons in brain motor areas. Currently there is no cure for PD, and traditional animal models of PD inadequately mimic the early cellular events involved in the progressive destruction of dopaminergic neurons. In collaboration with clinicians, industry partners, and other academic institutions in the U.S.A., we are developing a new rat PD model that better reflects the physiology of the aging brain. We aim to characterize how elevation of the brain chemical adenosine triggers loss of dopaminergic nerves, and to study stem cell transplantation as a critical first step in developing a combinatorial treatment that will ultimately help the aging population living with PD.

C. Binding of Endophilin Endocytic Proteins to AMPA Receptors and Neuronal Voltage-gated Potassium (Kv) Channels

Increasing evidence suggest that some proteins normally involved in the recycling of tiny membrane vesicles can regulate the density of specific membrane receptors and ion channels present on the surfaces of nerve cells. The recycling proteins of the endophilin-family contain a specific region that preferentially binds to protein sequences enriched with proline amino acids.  Endophilin proteins are also known to bind to other endocytic protein machineries, including dynamin 2, and to the immediate-early gene called Arc/Arg3.1 (Arc), which also serves as a marker for recently activated nerve cells.  Arc has also been shown to regulate the surface expression of AMPARs, and genetic ablation of Arc leads to memory retention deficits. Recently we reported that the adenosine A1 receptor (A1R) causes clathrin-mediated internalization of AMPARs, which underlies A1R-mediated reduction in hippocampal synaptic transmission. 

However, it is not yet known whether a similar mechanism for endophilin-Arc-driven AMPAR internalization also occurs for Kv-family of potassium channels (Kv1.5, Kv4.2, HERG) in the brain.  Since the cytoplasmic regions of some Kv channels contain appropriate patterns for endophilin binding, we will investigate the possibility that some Kv channels are directly coupled to endophilin. This interaction can facilitate the recycling of these Kv channels to and from the nerve surface, which can affect nerve excitability and action of memory-forming molecules, such as the AMPARs. In long term, this work will assist in the evaluation of specific potassium channels as targets to prevent excessive neuronal excitability, such as seen with seizures and subsequent memory loss.

D. Impact of Infiltrating Immune Cells in Stroke Damage

The precise cellular mechanisms underlying the delayed neuronal cell death after the initial stroke event remains a mystery. Our lab recently reported (Chen et al., J Neurosci, 2014; Stockwell et al., Neuropharm, 2016) that the molecule called adenosine plays a crucial role in hippocampal neuronal damage in an animal model of stroke. It was also recognized in this animal stroke model that peripheral immune cells (e.g., neutrophils and macrophages) and the brain’s resident immune cells called the microglia accumulate near the injury site in the cortex leading to complete loss of neurons in the immediate site of cortical injury (Cayabyab et al., J Neurosci Res, 2013). However, it remains to be established whether adenosine and increased neurotoxic and inflammatory factors are causing damage to the endothelium of the blood brain barrier (BBB), making the brain more susceptible to infiltration from peripheral immune cells that ultimately causes hyper-inflammation that is harmful to neurons in brain-sensitive areas, such as the hippocampus.

We will test the hypothesis that adenosine plays a major role in enhancing the migration of peripheral immune cells, such as neutrophils, macrophages and lymphocytes, into the brain after inducing a stroke or mimicking a stroke-like condition in animal studies.  Using animal stroke models and imaging microscopy analyses, we will determine whether blocking specific adenosine receptors in the periphery as well as inside the brain will be effective in reducing the “leakiness” of the BBB, and hence reduce hippocampal neuronal damage. The expected major outcome --reduced immune cell infiltration leading to reduced brain damage after stroke-- will greatly impact the aging population in our province, as excessive inflammation is a hallmark feature of silent strokes and vascular dementia- two aging-related neurological diseases prevalent in Saskatchewan.

E. Molecular Switches Promoting HERG Ion Channel Expression in Human Breast Cancers

Breast cancer remains a complex disease process and its incidence is increasing worldwide.  Human breast cancer cells can arise when molecular switches in breast tissue become hyperactive, resulting in uncontrolled proliferation.  In some cases, hormone replacement therapy has been associated with increased incidence of human breast cancers.  The hormone estrogen is a major factor in regulating cell division and proliferation, and promotes gene expression by activating intracellular messengers or switches, including STATs (signal transducer and activator of transcription).  Also in recent years, emerging evidence suggest the potassium ion channel called HERG is over-expressed in many types of cancer cells and our pilot studies provide new evidence linking HERG channel over-expression with activation of STATs. 

The current study previously funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region will use cutting-edge imaging technology, biochemical and electrophysiological techniques, and human breast cancer cells to determine how estrogen triggers HERG expression and cancer cell growth to ultimately identify new anti-cancer drug targets that inhibit breast tumors.

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Current Trainees:
Graduate Students:

• Jocelyn Stockwell (PhD Candidate) – Adenosine Signaling in Animal Models of Neurodegenerative Diseases
• Elisabet Jakova (PhD Candidate) – Caffeine-based Dimer Compounds as Novel Neuroprotective Therapy in Animal Models of Parkinson’s Disease
• Adelaide Amah (MSc Candidate) – Repurposing Metformin, a Type 2 Diabetic drug, for Parkinson’s Disease
• Michael Zaki (MSc Candidate) – New Roles for Leukocyte Specific Protein 1 (LSP1) in Normal CNS Functions and in Animal Models of Stroke
• Jay Kim (MSc Candidate) – Therapeutic Potential of Low Field Magnetic Stimulation in Stroke
• Siyi He (MSc Candidate) – Epigenetic Regulation of HERG Channels in Cancer Cells
• Javeria Muhammadzai (MSc candidate, co-supervised) – Regulation of ENT1 Adenosine Transporters and PPARgamma by Adenosine A1 Receptors in Cancer
• Dr. Le Gui (PhD) – Electrophysiological Analyses of HERG Currents in Breast Cancer Cell Lines

Undergraduate Students:

• Ava Bayat (Honours Student) – Regulation of HCN Channels by Adenosine A1 Receptor Signaling in Rat Hippocampus
• Javeria Muhammadzai (Honours Student) – Regulation of ENT1 Adenosine Transporters by CK2 and Adenosine A1 Receptors in Human Breast Cancers
• Deepa George (Honours Student) – Role of HERG-STAT1 Interaction in Human Prostate Cancer Cell Proliferation

Past Trainees:
Graduate Students and Postdocs

• Dr. Yuncheng Lyu (PhD) – Cross-talk Between ABCA1 Cholesterol Transporter and Mitochondrial Function in Adenosine A1 Receptor-induced Parkinson’s Disease Model; Faculty, University of South China
• Xin (Ivan) Qin (MSc) – Transient Post-Hypoxia Insertion of Calcium-permeable AMPARs Contributes to Hippocampal Neurodegeneration
• Dr. Zhicheng Chen (PhD) – Postdoctoral Fellow at Harvard Medical School; Lead Scientist, Applied Biological Materials Inc. (BC, Canada)
• Min Yong (Kevin) Jung (MSc) – HERG Potassium Channel Regulation in Human Breast Cancer Cells
• Nicole Longmuir (MSc) – Currently in third year Medicine at the University of Saskatchewan
• Dr. Zhi Ming (PhD)
• Dr. Yosef Avchalumov (PhD)

Undergraduate Students (selected)

• Jasleen Saini (Honours and Summer Undergraduate Research Assistant) – Adenosine signaling and epilepsy. Recipient of NSERC USRA Award (2017) and Interdisciplinary Undergraduate Research Scholarship, UofS (2018)
• Olivia Friesen (Honours and Summer Undergraduate Research Assistant) – Microglia Activation in a Stroke-like Animal Model Is Associated with Animal Learning Impairments.  Recipient of NSERC USRA Award (2016)
• Ryan Teneycke (Summer Undergraduate Research Assistant) – Prevention of Neutrophil Infiltration to the Brain after Stroke by Chemokine Receptor Peptide Antagonist
• Siddarth Nosib
• Cherry Xiong (Honours undergraduate) – HERG and Breast Cancer Confocal Imaging. Currently in Family Medicine
• Mina Niazi (Summer Undergraduate Student, and Dean’s Summer Student) – Adenosine and AMPAR trafficking.  Currently in Internal Medicine

Techniques used in my lab includes:
CFI-funded LSM 700 confocal microscope, electrophysiology (fEPSP extracellular recording, patch clamp recording), biochemistry (co-immunoprecipitation, GST-pulldown assays, biotinylation, Western blotting), animal models of stroke and Parkinson’s disease, in vivo model of breast and prostate cancers, behavioural assays for learning and motor behaviours, low field transmagenetic.

Collaborators:

• Dr. Chao-Ke Tang (University of South China, China) – Cholesterol transporters in atherosclerosis and breast cancers.
• Dr. Ivar Mendez (Department of Surgery, University of Saskatchewan) – Development of Novel Animal Model of Parkinson’s Disease; Use of Stem Cell Therapy in Stroke and Parkinson’s disease
• Dr. Michael Kelly (Surgery), Dr. Lixin Liu (Pharmacology), Dr. Wolfgang Walz (Psychiatry), and Dr. John Gordon (Medicine) – Role of Peripheral Immune Cell Infiltration to Stroke Damage
• Dr. Yanbo Zhang (Psychiatry) – Preclinical studies of low field transmagnetic stimulation in neurodegenerative diseases
• Dr. Mohan Babu (Biochemistry, University of Regina) – Protein-protein interactions of HERG in cancer; Mitochondrial dysfunction in neurodegeration

Media coverage:
CBC interview
The Sheaf newspaper
University Communications Press Release
CTV Morning Live Features Dr. Francisco Cayabyab for Breast Cancer Awareness Month

• Gao, A., Cayabyab, F.S., Chen, X., Yang, J., Wang, L., Peng, T., and Lv, Y. Implications of sortilin in lipid metabolism and lipid disorder diseases.  DNA and Cell Biology. 2017 Dec; 36(12)-1050-1061, doi: 10.1089/dna.2017.3853.  Epub Sep 25, 2017
• Stockwell, J., Jakova, E., and Cayabyab, F.S.  Adenosine A1 and A2A receptors in the brain: current research and their role in neurodegeneration. Molecules, 22(4), pii: E676. doi: 10.3390/molecules22040676, 2017.  Epub April 23, 2017
• Walz, W., and Cayabyab, F.S. Neutrophil infiltration and matrix metalloproteinase-9 in lacunar infarction. Neurochemical Research. 2017 Sep; 42(9):2560-2565, doi:10.1007/s11064-017-2265-1, 2017. Epub April 18, 2017
• Chen Z, Stockwell J, Cayabyab FS. Adenosine A1 Receptor-Mediated Endocytosis of AMPA Receptors Contributes to Impairments in Long-Term Potentiation (LTP) in the Middle-Aged Rat Hippocampus. Neurochem Res. 2015 Dec 23. [Epub ahead of print] PMID: 26700433
• Stockwell J, Chen Z, Niazi M, Nosib S, Cayabyab FS. Protein phosphatase role in adenosine A1 receptor-induced AMPA receptor trafficking and rat hippocampal neuronal damage in hypoxia/reperfusion injury. Neuropharmacology. 2016 Mar;102:254-65. doi: 10.1016/j.neuropharm.2015.11.018. Epub 2015 Nov 25. PMID: 26626486
• Hossain M, Qadri SM, Xu N, Su Y, Cayabyab FS, Heit B, Liu L. Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression. J Immunol. 2015 Sep 1;195(5):2408-16. doi: 10.4049/jimmunol.1402225. Epub 2015 Aug 3. PMID: 26238489
• Lv YC, Yang J, Yao F, Xie W, Tang YY, Ouyang XP, He PP, Tan YL, Li L, Zhang M, Liu D, Cayabyab FS, Zheng XL, Tang CK. Diosgenin inhibits atherosclerosis via suppressing the MiR-19b-induced downregulation of ATP-binding cassette transporter A1. Atherosclerosis. 2015 May;240(1):80-9. doi: 10.1016/j.atherosclerosis.2015.02.044. Epub 2015 Feb 24. PMID: 25765596
• Li Y, He PP, Zhang DW, Zheng XL, Cayabyab FS, Yin WD, Tang CK. Lipoprotein lipase: from gene to atherosclerosis. Atherosclerosis. 2014 Dec;237(2):597-608. doi: 10.1016/j.atherosclerosis.2014.10.016. Epub 2014 Oct 18. Review. PMID: 25463094
• Qadri SM, Su Y, Cayabyab FS, Liu L. Endothelial Na+/H+ exchanger NHE1 participates in redox-sensitive leukocyte recruitment triggered by methylglyoxal. Cardiovasc Diabetol. 2014 Sep 30;13:134. doi: 10.1186/s12933-014-0134-7. PMID: 25270604 Free PMC Article
• Lin HB, Cadete VJ, Sra B, Sawicka J, Chen Z, Bekar LK, Cayabyab F, Sawicki G. Inhibition of MMP-2 expression with siRNA increases baseline cardiomyocyte contractility and protects against simulated ischemic reperfusion injury. Biomed Res Int. 2014;2014:810371. doi: 10.1155/2014/810371. Epub 2014 Jul 24. PMID: 25147815 Free PMC Article
• Lv YC, Tang YY, Peng J, Zhao GJ, Yang J, Yao F, Ouyang XP, He PP, Xie W, Tan YL, Zhang M, Liu D, Tang DP, Cayabyab FS, Zheng XL, Zhang DW, Tian GP, Tang CK. MicroRNA-19b promotes macrophage cholesterol accumulation and aortic atherosclerosis by targeting ATP-binding cassette transporter A1. Atherosclerosis. 2014 Sep;236(1):215-26. doi: 10.1016/j.atherosclerosis.2014.07.005. Epub 2014 Jul 18. PMID: 25084135
• Yu XH, Cui LB, Wu K, Zheng XL, Cayabyab FS, Chen ZW, Tang CK. Hydrogen sulfide as a potent cardiovascular protective agent. Clin Chim Acta. 2014 Nov 1;437:78-87. doi: 10.1016/j.cca.2014.07.012. Epub 2014 Jul 21. Review. PMID: 25058799
• Chen Z, Xiong C, Pancyr C, Stockwell J, Walz W, Cayabyab FS. Prolonged adenosine A1 receptor activation in hypoxia and pial vessel disruption focal cortical ischemia facilitates clathrin-mediated AMPA receptor endocytosis and long-lasting synaptic inhibition in rat hippocampal CA3-CA1 synapses: differential regulation of GluA2 and GluA1 subunits by p38 MAPK and JNK. J Neurosci. 2014 Jul 16;34(29):9621-43. doi: 10.1523/JNEUROSCI.3991-13.2014. PMID: 25031403 Free Article
• Su Y, Qadri SM, Cayabyab FS, Wu L, Liu L. Regulation of methylglyoxal-elicited leukocyte recruitment by endothelial SGK1/GSK3 signaling. Biochim Biophys Acta. 2014 Nov;1843(11):2481-91. doi: 10.1016/j.bbamcr.2014.06.018. Epub 2014 Jul 5. PMID: 25003317 Free Article
• Lin HB, Sharma K, Bialy D, Wawrzynska M, Purves R, Cayabyab FS, Wozniak M, Sawicki G. Inhibition of MMP-2 expression affects metabolic enzyme expression levels: proteomic analysis of rat cardiomyocytes. J Proteomics. 2014 Jun 25;106:74-85. doi: 10.1016/j.jprot.2014.04.026. Epub 2014 Apr 24. PMID: 24769238
• Zhang M, Wu JF, Chen WJ, Tang SL, Mo ZC, Tang YY, Li Y, Wang JL, Liu XY, Peng J, Chen K, He PP, Lv YC, Ouyang XP, Yao F, Tang DP, Cayabyab FS, Zhang DW, Zheng XL, Tian GP, Tang CK. MicroRNA-27a/b regulates cellular cholesterol efflux, influx and esterification/hydrolysis in THP-1 macrophages. Atherosclerosis. 2014 May;234(1):54-64. doi: 10.1016/j.atherosclerosis.2014.02.008. Epub 2014 Feb 21. PMID: 24608080
• Yu XH, Jiang N, Zheng XL, Cayabyab FS, Tang ZB, Tang CK. Interleukin-17A in lipid metabolism and atherosclerosis. Clin Chim Acta. 2014 Apr 20;431:33-9. doi: 10.1016/j.cca.2014.01.012. Epub 2014 Feb 6. Review. PMID: 24508995
• Wu JF, Wang Y, Zhang M, Tang YY, Wang B, He PP, Lv YC, Ouyang XP, Yao F, Tan YL, Tang SL, Tang DP, Cayabyab FS, Zheng XL, Zhang DW, Zeng GF, Tang CK. Growth differentiation factor-15 induces expression of ATP-binding cassette transporter A1 through PI3-K/PKCζ/SP1 pathway in THP-1 macrophages. Biochem Biophys Res Commun. 2014 Feb 14;444(3):325-31. doi: 10.1016/j.bbrc.2014.01.048. Epub 2014 Jan 22. PMID: 24462860
• Zhao GJ, Tang SL, Lv YC, Ouyang XP, He PP, Yao F, Tang YY, Zhang M, Tang YL, Tang DP, Cayabyab FS, Tian GP, Tang CK. NF-κB suppresses the expression of ATP-binding cassette transporter A1/G1 by regulating SREBP-2 and miR-33a in mice. Int J Cardiol. 2014 Feb 15;171(3):e93-5. doi: 10.1016/j.ijcard.2013.11.093. Epub 2013 Dec 7. No abstract available. Erratum in: Int J Cardiol. 2014 Sep 20;176(2):e76. PMID: 24360166
• Tian GP, Tang YY, He PP, Lv YC, Ouyang XP, Zhao GJ, Tang SL, Wu JF, Wang JL, Peng J, Zhang M, Li Y, Cayabyab FS, Zheng XL, Zhang DW, Yin WD, Tang CK. The effects of miR-467b on lipoprotein lipase (LPL) expression, pro-inflammatory cytokine, lipid levels and atherosclerotic lesions in apolipoprotein E knockout mice. Biochem Biophys Res Commun. 2014 Jan 10;443(2):428-34. doi: 10.1016/j.bbrc.2013.11.109. Epub 2013 Dec 2. PMID: 24309104
• Yu XH, Jiang N, Yao PB, Zheng XL, Cayabyab FS, Tang CK. NPC1, intracellular cholesterol trafficking and atherosclerosis. Clin Chim Acta. 2014 Feb 15;429:69-75. doi: 10.1016/j.cca.2013.11.026. Epub 2013 Dec 1. Review. PMID: 24296264
• Yu XH, Qian K, Jiang N, Zheng XL, Cayabyab FS, Tang CK. ABCG5/ABCG8 in cholesterol excretion and atherosclerosis. Clin Chim Acta. 2014 Jan 20;428:82-8. doi: 10.1016/j.cca.2013.11.010. Epub 2013 Nov 16. Review. PMID: 24252657
• Cayabyab FS, Gowribai K, Walz W. Involvement of matrix metalloproteinases-2 and -9 in the formation of a lacuna-like cerebral cavity. J Neurosci Res. 2013 Jul;91(7):920-33. doi: 10.1002/jnr.23223. Epub 2013 Apr 22. PMID: 23606560