
Mark P. de Caestecker, M.D., Ph.D.
- Assistant Professor of Medicine (Nephrology)
Phone
S-3223 Medical Center North
Nashville, TN 37232
Mark P. de Caestecker, M.D., Ph.D.
- Assistant Professor of Medicine (Nephrology)
615-343-2844
mark.de.caestecker@vumc.org
S-3223 Medical Center North
Nashville, TN 37232
Research Program
Departments/Affiliations
Profile
Education
Research Emphasis
Kidney regeneration and therapy, kidney development, retinoic acid signaling, immune cells, macrophages, pulmonary vasculature, genetics, BMP signaling, endothelial cells
Research Description
Our laboratory is interested in the mechanisms and therapeutic manipulation of pathways and cellular responses involved in promoting healthy cellular repair after organ injury, with a particular focus on the transition of acute kidney injury to fibrosis and chronic kidney disease. Our current focus includes:
a) Phenotypic screening for small molecules that promote proliferative repair of damaged epithelium after injury. These studies are based on a long-term collaboration with Dr. Neil Hukriede from the University of Pittsburgh, who has developed a phenotypic screen in zebrafish to identify compounds that promote proliferative expansion of nephron progenitor cells. Using this approach we have identified a new family of highly selective HDAC inhibitors that promote non-scarring repair after acute kidney injury, that are effective in multiple toxic and surgical models of kidney injury, and importantly, are effective when given days after the initiating injury. We are currently working on target identification and SAR for optimization.
b) Studying the regulation, role and therapeutic manipulation of retinoic acid signaling in promoting effective repair after acute kidney injury. We are studying the cellular origins and effectors of retinoic acid signaling activity after acute kidney injury; exploring the role of immune effectors in mediating these effects; and develop new, non-toxic therapeutic approaches to enhance this natural response and promote effective repair after kidney injury.
Our laboratory also studies the role of BMP signaling in pulmonary hypertension. Human genetic studies indicate that this signaling pathway plays an important role in modifying pulmonary vascular responses in disease. We have shown that Bmp signaling exerts distinct opposing, cell specific effects on pulmonary vascular remodeling and tone. We are currently using genetic models in mice as well as patient derived cells to evaluate effect of inherited mutations in the BMP type 2-receptor, BMPR2, on pulmonary vascular cell function. Our specific focus is on how these mutations affect endothelial cell function, specifically metabolic function and perivascular inflammation, and how these pathologic responses promote pulmonary hypertension in genetically modified mice.
Publications
- Hukriede N, Vogt A, de Caestecker M. Drug Discovery to Halt the Progression of Acute Kidney Injury to Chronic Kidney Disease: A Case for Phenotypic Drug Discovery in Acute Kidney Injury. Nephron [print-electronic]. 2017 Jun 6/15/2017; PMID: 28614822, PII: 000476079, DOI: 10.1159/000476079, ISSN: 2235-3186.
- Frump AL, Datta A, Ghose S, West J, de Caestecker MP. Genotype-phenotype effects of Bmpr2 mutations on disease severity in mouse models of pulmonary hypertension. Pulm Circ. 2016 Dec; 6(4): 597-607. PMID: 28090303, PMCID: PMC5210048, PII: PC2013387, DOI: 10.1086/688930, ISSN: 2045-8932.
- Skrypnyk NI, Voziyan P, Yang H, de Caestecker CR, Theberge MC, Drouin M, Hudson B, Harris RC, de Caestecker MP. Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury. Am. J. Physiol. Renal Physiol [print-electronic]. 2016 Aug 8/1/2016; 311(2): F268-77. PMID: 27194713, PMCID: PMC5008672, PII: ajprenal.00056.2016, DOI: 10.1152/ajprenal.00056.2016, ISSN: 1522-1466.
- West JD, Voss BM, Pavliv L, de Caestecker M, Hemnes AR, Carrier EJ. Antagonism of the thromboxane-prostanoid receptor is cardioprotective against right ventricular pressure overload. Pulm Circ. 2016 Jun; 6(2): 211-23. PMID: 27252848, PMCID: PMC4869926, PII: PC2013314, DOI: 10.1086/686140, ISSN: 2045-8932.
- Skrypnyk NI, Siskind LJ, Faubel S, de Caestecker MP. Bridging translation for acute kidney injury with better preclinical modeling of human disease. Am. J. Physiol. Renal Physiol [print-electronic]. 2016 May 5/15/2016; 310(10): F972-84. PMID: 26962107, PMCID: PMC4889323, PII: ajprenal.00552.2015, DOI: 10.1152/ajprenal.00552.2015, ISSN: 1522-1466.
- Chiba T, Skrypnyk NI, Skvarca LB, Penchev R, Zhang KX, Rochon ER, Fall JL, Paueksakon P, Yang H, Alford CE, Roman BL, Zhang MZ, Harris R, Hukriede NA, de Caestecker MP. Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI. J. Am. Soc. Nephrol [print-electronic]. 2016 Feb; 27(2): 495-508. PMID: 26109319, PMCID: PMC4731115, PII: ASN.2014111108, DOI: 10.1681/ASN.2014111108, ISSN: 1533-3450.
- King T, de Caestecker M, Lowery JW. Reply to "Bone morphogenetic protein's contribution to pulmonary artery hypertension". Surg Neurol Int. 2016; 7: 91. PMID: 27857855, PMCID: PMC5093875, PII: SNI-7-91, DOI: 10.4103/2152-7806.192635, ISSN: 2229-5097.
- Skrypnyk NI, Sanker S, Brilli-Skvarca L, Novitskaya T, Woods C, Chiba T, Patel K, Goldberg ND, McDermott L, Vinson PN, Calcutt MW, Huryn DM, Vernetti LA, Vogt A, Hukriede N, de Caestecker MP. Delayed treatment with PTBA analogs reduces post injury renal fibrosis after kidney injury. Am. J. Physiol. Renal Physiol [print-electronic]. 2015 Dec 12/9/2015; ajprenal.00503.2015. PMID: 26661656, PMCID: PMC4835925, PII: ajprenal.00503.2015, DOI: 10.1152/ajprenal.00503.2015, ISSN: 1522-1466.
- de Caestecker M, Humphreys BD, Liu KD, Fissell WH, Cerda J, Nolin TD, Askenazi D, Mour G, Harrell FE, Pullen N, Okusa MD, Faubel S, . Bridging Translation by Improving Preclinical Study Design in AKI. J. Am. Soc. Nephrol [print-electronic]. 2015 Dec; 26(12): 2905-16. PMID: 26538634, PMCID: PMC4657852, PII: ASN.2015070832, DOI: 10.1681/ASN.2015070832, ISSN: 1533-3450.
- Cirio MC, de Caestecker MP, Hukriede NA. Zebrafish Models of Kidney Damage and Repair. Curr Pathobiol Rep [print-electronic]. 2015 Jun; 3(2): 163-70. PMID: 28690924, PMCID: PMC5497754, DOI: 10.1007/s40139-015-0080-4, ISSN: 2167-485X.