Ravi Goyal, MD, PhD
Division of Pharmacology
School of Medicine
Loma Linda University
Loma Linda, CA 92350
Phone: (909) 558-4352
Fax: (909) 558-4029
Despite groundbreaking work in defining the genetic and epigenetic basis for cancer, hypertension, type-2 diabetes, neurodegenerative disorders, and other clinical conditions; therapies still remain palliative. I amd attempting to develop an innovative approach to treat underlying epigenetic defects (promoter DNA methylation/demethylation) common to these disorders. Several studies have demonstrated significant changes in DNA methylation, which switches DNA between Hetrochromatin and Euchromatin, an important factor in the pathogenesis of these disorders. Furthermore, hypermethylation of Angiotensin Converting Enzyme, BRACA1, p53, and hypomethylation of c-myc, ras, and other genes involved in these disorders, provide rationale to devise therapies that targets DNA methylation. During the past several decades, attempts have been made to target DNA methylation by pharmacological agents such as 5-aza-2'-deoxycytidine, arabinofuranosyl-5-azacytosine, MG-98 and others. Cell/Gene specificity provides the single greatest challenge, however. We have developed an innovative approach to overcome this. The potential to translate these approaches to the bedside, is a the major strategic plan. We start with identifying the alterations in promoter DNA methylation with diseases. Then with novel zinc finger proteins, which can recognize specific DNA sequences, we are conducting experiments to fuse methylase or demethylase enzymes, and attempt to change methylation in a desired direction, in both cell culture and animal models, to achieve the promise of gene therapy. The approaches are not limited to the diseases mentioned above; they will be beneficial in future research in many ways. For instance, it will help to fulfill the dream of stem cell therapy by directing cellular differentiation, generating epigenetic transgenic mice strains by selectively targeting, at the embryonic stage, promoter DNA methylation of a single gene at specific CpG Island. Importantly, the ability to selectively modify promoter DNA methylation, as a therapy in vivo, could revolutionize the treatment of diverse genetic diseases, and fulfill the therapeutic promise of the Human Genome Project.
The second project is to elucidate the mechanisms involved in long-term hypoxia acclimatization. As widely accepted, in response to hypoxia exposure, hypoxia inducible factor 1α (HIF1α) plays a crucial role in cell survival. Notably, with long-term hypoxia exposure HIF1α levels returns to the basal level. Mechanisms are not known, however. Moreover, silencing of HIF1α in the acute phase of hypoxia abolishes the long-term hypoxia-induced up-regulation of a number of genes. Thus, HIF1α appears to be crucial in long-term regulation of these genes, despite its return to the basal level with continued hypoxia. This may be possible through epigenetic modifications of the DNA by HIF1α. Thus, to elucidate HIF1α-mediated long-term gene regulation and to gain mechanistic insights, we are currently examining HIF1α induced transcriptional epigenetic changes and cellular adaptive responses. Furthermore, our studies demonstrate post-translational phosphorylation of ERK with chronic hypoxia. In the current studies we are conducting experiment to test the hypothesis that hypoxia exposure leads to HIF1α-mediated changes in the gene expression by transcriptional epigenetic regulation. We also are working on the associated hypothesis that retrograde mitochondrial signaling is involved in the constitute ERK phosphorylation.
- Eugenia Mata-Greenwood, Dipali Goyal, and Ravi Goyal. comparative and Experimental Studies on the Genes Altered by Chronic Hypoxia in Human Brain Microendothelial Cells. Front. Physiol. https://doi.org/10.3389/fphys.2017.00365 (ahead of print)
- Kumar M and Goyal R. LincRNA as a Therapeutic Target for Angiogenesis. Current Topics in Medicinal Chemistry, 2017:17:1-8. PMID: 27848894
- Goyal R., Goyal D, Longo, LD, Clyman R. Microarray gene expression analysis in ovine ductus arteriosus during fetal development and birth transition. Pediatric Research. 2016 PMID: 27356085.
- Goyal R, Billings TL, Mansour T, Martin C, Baylink D, Longo LD, Pearce WJ, Mata-Greenwood E. Vitamin D status and metabolism in an ovine pregnancy model: effect of long-term high-altitude hypoxia. AJP endocrinology. 2016;310:E1062-71. PMID: 27143557.
- Giang M. Papamatheakis DG, Nguyen D, Paez, R, Johnston CB, Kim J, Brunnell A, Blood Q, Goyal R, Longo LD, Wilson SM. Muscarinic-receptor activation affects pulmonary artery contractility in sheep: the impact of maturation and chronic hypoxia on endothelial-dependent and -independent function. High Altitude Medicine. 2016 June; 17(2):122-32. PMID: 27281473.
- Goyal R, Goyal D, Longo LD. Metabolic Profiles in Ovine Carotid Arteries with Development and Long-Term Hypoxia. Plos One, 2015, Jun 25;10(6):e0130739. PMID 26110419
- Jang EA, Longo LD, Goyal R. Antenatal maternal hypoxia: Criterion for fetal growth restriction in rodents. Front Physiol 2015;6:176. PMID 26106333.
- Goyal R, Van-Wickle J, Goyal D, Longo LD. Antenatal maternal low protein diet: ACE-2 in the mouse lung and sexually dimorphic programming of hypertension. BMC Physiol. 2015 May 14;15(1):2. doi: 10.1186/s12899-015-0016-6. PMID: 25971747.
- Dobyns AE, Goyal R, Carpenter LG, Freeman TC, Longo LD, Yellon SM. Macrophage Gene Expression Associated with Remodeling of the Prepartum Rat Cervix:Microarray and Pathway Analysis. PLoS One, 2015 10(3):e0119782.PMCID: PMC4374766.
- Goyal R, Goyal D, Chu N, Van Wickle J, Longo LD. Cerebral Artery Alpha-1 AR Subtypes: High Altitude Long-Term Acclimatization Responses. PLoS One, 2014 9(11): e112784. PMID: 25393740
- Goyal R, Longo LD. Acclimatization to Long-Term Hypoxia: Gene Expression in Ovine Carotid Arteries. Physiol Genomics, 2014, 1;46(19):725-34. PMID: 25052263
- Goyal R, Zhang L, Blood AB, Baylink DJ, Longo LD, Oshiro B, Mata-Greenwood E. Characterization of an animal model of pregnancy-induced vitamin D deficiency due to metabolic gene dysregulation. Am J of Physiol Endocrinol Metab, 306:E256-66, 2014. PMID: 24326417
- Goyal R, Van Wickle J, Goyal D, Matei N, Longo LD. Antenatal maternal long-term hypoxia: acclimatization responses with altered gene expression in ovine fetal carotid arteries. Plos One, 2013. PMID: 24367503
- Goyal R, Wong C, Wickle, JV, Longo LD. Antenatal maternal protein deprivation: Sexually dimorphic programming of the pancreatic renin-angiotensin system. J. Ren Ang Ald Sys. 14:137-145, 2013. PMID: 22898440
- Goyal R and Longo LD. Maternal Protein Deprivation: Sexually Dimorphic Programming of Hypertension in the Mouse. Hypertension Res. 36:29-35, 2013. PMID: 22932874
- Longo LD and Goyal R. Cerebral Artery Signal Transduction Mechanisms: Developmental Changes in Dynamics and Ca2+ Sensitivity. Current Vascular Pharmacology, 2013 11(5):655-711. PMID: 24063382
- Goyal R and Longo LD. Gene Expression in Sheep Carotid Arteries: Major Changes with Maturational Development. Pediatric Res. 72:137-46, 2012. PMID: 22565503
- Hartman RE, Kamper J, Goyal R, Stewart JM, Longo LD. Motor and Cognitive Deficits in Mice Bred to have Low or High Blood Pressure. Physiology and Behavior. 105:1092-1097, 2012. PMID: 22154805
- Goyal R, Henderson DA, Chu, N, Longo LD. Ovine Middle Cerebral Artery Characterization and Quantification of Ultrastructure and Other Features: Changes with Development. Am J Physiol Regul Integr Comp Physiol. 302:R433-445, 2012. PMID: 22116510
- Goyal, R., Papamatheakis, D., Loftin, M., Vranchken, K., Dawson, A., Osman, N., Blood, AB, Pearce, W., Longo, L. & Wilson, S. (2011c) Long-Term Maternal Hypoxia: The Role of Extracellular Ca2+ Entry During Serotonin-Mediated Contractility in Fetal Ovine Pulmonary Arteries. Reprod Sci. 18:948-62, 2011. PMID: 21960509
- Papamatheakis DG, Vemulakonda S, Blood Q, Goyal R, Rbalcava M, Vrancken K, Bennett A, Dawson A, Osman NJ, Blood AB, Pearce WJ, Longo LD, Wilson SM. Preservation of serotonin-mediated contractility in adult sheep pulmonary arteries following long-term high-altitude hypoxia. High Alt Med Biol. 12:253-64, 2011. PMID: 21962069
- Goyal R, Lister R, Leitzke A, Goyal D, Gheorghe CP, Longo LD. Antenatal Maternal Hypoxic Stress: Adaptations of the Placental Renin-Angiotensin System in Mouse. Placenta 32:134-9, 2010. PMID: 21130492
- Goyal R, Leitzke A, Goyal D, Gheorghe CP, Longo LD. Antenatal Maternal Hypoxic Stress: Adaptations in Fetal Lung Renin-Angiotensin System. Reproductive Sci. 18(2):180-189, 2011. PMID: 20978179
- Goyal R, Mittal A, Chu N, Arthur RA, Zhang L, Longo LD. Maturation and Long-Term Hypoxia-Induced Acclimatization Responses in PKC-Mediated Signaling Pathways in Ovine Cerebral Arterial Contractility. Am J Physiol, 299:R1377-86, 2010. PMID: 20702800
- Goyal R, Mittal A, Chu N, Zhang L, Longo LD. Alpha1-Adrenergic Receptor Subtype Function in Fetal and Adult Cerebral Arteries. Am J Physiol, 298:H1797-806, 2010. PMID: 20348219
- Goyal R, Yellon S, Longo LD, Greenwood EM, Placental gene expression in a rat 'model' of placental insufficiency. Placenta, 31:568-575, 2010. PMID: 20621762
- Gheorghe CP, Goyal R, Mittal AS, and Longo LD. Gene expression in the placenta: Maternal stress and epigenetic responses. Intl J Devel Biol, 54:507-523, 2010. PMID: 19876832
- Goyal R, Goyal D, Leitzke A, Longo L.D. Brain renin-angiotensin system: Fetal epigenetic programming by maternal low protein diet. Reprod Sci, 17:227-238, 2010. PMID: 19923380
- Goyal R, Galffy A, Fields, SA, Mittal A, Longo LD. Maternal protein deprivation-mediated alterations in systemic renin-angiotensin system in fetal mice. Reprod Sci, 16:894-904, 2009. PMID: 19516079
- Goyal R, Angermann JE, Ostrovskaya O, Buchholz JN, Smith GD, Wilson, SM. Enhanced capacitative calcium entry and sarcoplasmic-reticulum calcium storage capacity with advanced age in murine mesenteric arterial smooth muscle cells. Exp Gerontol 44:201-207, 2009. PMID: 19017540
- Gheorghe CP, Goyal R, Holweger JK, and Longo LD. Placental gene expression responses to maternal protein restriction in the mouse. Placenta, 30(5):411-7, 2009. PMID: 19362366.
- Goyal R, Mittal A, Chu N, Zhang L, Longo LD. Maturation and role of PKC-mediated contractility in ovine cerebral arteries Am J Physiol, 294:H2242-52, 2009. PMID: 19749163
- Goyal R, Creel KD, Chavis EJ, Smith GD, Longo LD and Wilson SM. Maturation of intracellular calcium homeostasis in sheep pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 295:L905-L914, 2008. PMID: 18776056
- Ostrovskaya O, Goyal R, Osman N, McAllister CE, Pessah IN, Hume JR and Wilson SM. Inhibition of ryanodine receptors by 4-(2-aminopropyl)-3,5-dichloro-N,N-ethylaniline (FLA 365) in canine pulmonary arterial smooth muscle cells. J Pharmacol Exp Ther 323:381-390, 2007. PMID: 17640951
PUBLISHED BOOK CHAPTERS
- Longo LD & Goyal R. The Stress of Chronic Hypoxia in Fetal Growth Restriction: Some Physiological Considerations. Stress and Developmental Programming of Health and Disease: Beyond Phenomenology. Nova Science Publishers. 2014 p. 131-168 https://www.novapublishers.com/catalog/product_info.php?products_id=51278
- Longo LD & Goyal R. Fetal Stress and Growth Restriction at High Altitude. Stress and Developmental Programming of Health and Disease: Beyond Phenomenology. Nova Science Publishers. 2014 p. 169-238 https://www.novapublishers.com/catalog/product_info.php?products_id=51278
- Longo LD, Zhang L, Goyal R. The Developing Brain: What is the Role of Antenatal Stress-Mediated Epigenetics? Stress and Developmental Programming of Health and Disease: Beyond Phenomenology. Nova Science Publishers. 2014 p. 239-340 https://www.novapublishers.com/catalog/product_info.php?products_id=51278
- Longo LD, Goyal R. Maternal Stress-Mediated Gene Expression Changes in the Mouse Placenta: A Mosaic Hypothesis of Epigenesis. In: Croy A, Yamada AT, DeMayo FJ, Adamson SL, editors. The Guide to Investigation of Mouse Pregnancy. Academic Press; Elsevier Inc. 2014. p. 443–462. http://www.sciencedirect.com/science/book/9780123944450#ancpt03Longo LD, Gheorghe CP, Goyal R. Dietary and Hypoxic Protocols That Alter Placental Gene Expression in Response to Maternal Stress. In: Croy A, Yamada AT, DeMayo FJ, Adamson SL, editors. The Guide to Investigation of Mouse Pregnancy. Academic Press; Elsevier Inc. 2014. p. 761–762. http://www.sciencedirect.com/science/book/9780123944450#ancpt03