Mark N. Gillespie, Ph.D.
Biography
Dr. Mark N. Gillespie, Professor, received his Baccalaureate in Physiology and Ph.D. in Pharmacology from the University of Kentucky in Lexington, KY, and completed his postdoctoral fellowship in the Cardiovascular Pulmonary Research Lab at the University of Colorado in Denver, CO. Dr. Gillespie chaired of the Department of Pharmacology at the Frederick P. Whiddon College of Medicine from 1995 to 2023.
Research
Research in the Gillespie laboratory focuses on defining novel biological roles of oxidative injury or modification to the two cellular genomes, mitochondrial (mt) and nuclear DNA, in governing the life and death of lung cells. One series of studies tests the idea that mtDNA functions as a "sentinel" molecule in which excessive damage caused by toxic oxygen radicals serves to activate cell death pathways. In an extension of this idea, we also are exploring the prospect that mtDNA repair pathways could emerge as isolated targets for pharmacologic intervention in acute lung injury. In contrast to oxidative damage to mtDNA, which occurs in the setting of toxicity, oxidants generated in the context of normal cell signaling do not alter mitochondrial DNA integrity, but surprisingly cause sequence-specific base modifications in nuclear genes. Because these oxidative modifications are clustered in promoter regions of inducible genes, our second major project tests the idea that oxidative DNA modifications accompanying physiological signals modify the topography and protein binding of functionally important DNA sequences and thereby influence gene regulation. This general hypothesis is tested experimental systems ranging in complexity from cultured lung cells to human lung tissue specimens from patients with COPD, idiopathic pulmonary hypertension, and other pulmonary disorders. These studies are significant because they have identified a new level of oxidant regulation of cell function at the level of the genome, and perhaps more importantly, because they point to links between normal cell signaling and somatic mutation underlying both malignant and non-malignant lung diseases.
Publications
Daly GT, Pastukh VM, Tan YB, Francis CM, Aggen CZ, Groark SC, Edwards C, Mulekar MS, Hamo M, Simmons JD, Kutcher ME, Hartsell EM, Dinwiddie DL, Turpin ZM, Bass HW, Roberts JT, Gillespie MN, Langley RJ. Novel attributes of cell-free plasma mitochondrial DNA in traumatic injury. Clin Transl Med. 2022 Oct;12(10):e1055. doi: 10.1002/ctm2.1055. PubMed PMID: 36245326; PubMed Central PMCID: PMC9574491.
Hepokoski ML, Odish M, Lam MT, Coufal NG, Rolfsen ML, Shadel GS, Moyzis AG, Sainz AG, Takiar PG, Patel S, Leonard AJ, Samandari N, Hansen E, Trescott S, Nguyen C, Jepsen K, Cutter G, Gillespie MN, Spragg RG, Sasik R, Ix JH. Absolute quantification of plasma mitochondrial DNA by droplet digital PCR marks COVID-19 severity over time during intensive care unit admissions. Am J Physiol Lung Cell Mol Physiol. 2022 Jul 1;323(1):L84-L92. doi: 10.1152/ajplung.00128.2022. Epub 2022 Jun 14. PubMed PMID: 35699291; PubMed Central PMCID: PMC9273271.
Hartsell EM, Gillespie MN, Langley RJ. Does acute and persistent metabolic dysregulation in COVID-19 point to novel biomarkers and future therapeutic strategies?. Eur Respir J. 2022 Feb;59(2). doi: 10.1183/13993003.02417-2021. Print 2022 Feb. PubMed PMID: 34675049; PubMed Central PMCID: PMC8542864.
Longnus SL, Rutishauser N, Gillespie MN, Reichlin T, Carrel TP, Sanz MN. Mitochondrial Damage-associated Molecular Patterns as Potential Biomarkers in DCD Heart Transplantation: Lessons From Myocardial Infarction and Cardiac Arrest. Transplant Direct. 2022 Jan;8(1):e1265. doi: 10.1097/TXD.0000000000001265. eCollection 2022 Jan. PubMed PMID: 34934807; PubMed Central PMCID: PMC8683216.
Langley RJ, Migaud ME, Flores L, Thompson JW, Kean EA, Mostellar MM, Mowry M, Luckett P, Purcell LD, Lovato J, Gandotra S, Benton R, Files DC, Harrod KS, Gillespie MN, Morris PE. A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure. Sci Rep. 2021 May 18;11(1):10515. doi: 10.1038/s41598-021-89716-0. PubMed PMID: 34006901; PubMed Central PMCID: PMC8131588.
Migaud M, Gandotra S, Chand HS, Gillespie MN, Thannickal VJ, Langley RJ. Metabolomics to Predict Antiviral Drug Efficacy in COVID-19. Am J Respir Cell Mol Biol. 2020 Sep;63(3):396-398. doi: 10.1165/rcmb.2020-0206LE. PubMed PMID: 32574504; PubMed Central PMCID: PMC7462337.
Williams JD, Houserova D, Johnson BR, Dyniewski B, Berroyer A, French H, Barchie AA, Bilbrey DD, Demeis JD, Ghee KR, Hughes AG, Kreitz NW, McInnis CH, Pudner SC, Reeves MN, Stahly AN, Turcu A, Watters BC, Daly GT, Langley RJ, Gillespie MN, Prakash A, Larson ED, Kasukurthi MV, Huang J, Jinks-Robertson S, Borchert GM. Characterization of long G4-rich enhancer-associated genomic regions engaging in a novel loop:loop 'G4 Kissing' interaction. Nucleic Acids Res. 2020 Jun 19;48(11):5907-5925. doi: 10.1093/nar/gkaa357. PubMed PMID: 32383760; PubMed Central PMCID: PMC7293029.
Rieske RR, Kutcher ME, Audia JP, Carter KT, Lee YL, Tan YB, Gillespie MN, Capley GC, Tatum DM, Smith AA, Duchesne JC, Simmons JD. Analysis of Plasma Products for Cellular Contaminants: Comparing Standard Preparation Methods. J Am Coll Surg. 2020 Apr;230(4):596-602. doi: 10.1016/j.jamcollsurg.2019.12.042. PubMed PMID: 32220451; PubMed Central PMCID: PMC7682813.
Tan YB, Pastukh VM, Gorodnya OM, Mulekar MS, Simmons JD, Machuca TN, Beaver TM, Wilson GL, Gillespie MN. Enhanced Mitochondrial DNA Repair Resuscitates Transplantable Lungs Donated After Circulatory Death. J Surg Res. 2020 Jan;245:273-280. doi: 10.1016/j.jss.2019.07.057. Epub 2019 Aug 14. PubMed PMID: 31421373; PubMed Central PMCID: PMC6900440.