Durga Devi Thota

All Publications

• California Stress, Trauma, and Resilience Study (CalSTARS) protocol: A multiomics-based cross-sectional investigation and randomized controlled trial to elucidate the biology of ACEs and test a precision intervention for reducing stress and enhancing resilience. Stress (Amsterdam, Netherlands) Kim, L. Y., Schüssler-Fiorenza Rose, S. M., Mengelkoch, S., Moriarity, D. P., Gassen, J., Alley, J. C., Roos, L. G., Jiang, T., Alavi, A., Thota, D. D., Zhang, X., Perelman, D., Kodish, T., Krupnick, J. L., May, M., Bowman, K., Hua, J., Liao, Y. J., Lieberman, A. F., Butte, A. J., Lester, P., Thyne, S. M., Hilton, J. F., Snyder, M. P., Slavich, G. M. 2024; 27 (1): 2401788

  Abstract

  Adverse Childhood Experiences (ACEs) are very common and presently implicated in 9 out of 10 leading causes of death in the United States. Despite this fact, our mechanistic understanding of how ACEs impact health is limited. Moreover, interventions for reducing stress presently use a one-size-fits-all approach that involves no treatment tailoring or precision. To address these issues, we developed a combined cross-sectional study and randomized controlled trial, called the California Stress, Trauma, and Resilience Study (CalSTARS), to (a) characterize how ACEs influence multisystem biological functioning in adults with all levels of ACE burden and current perceived stress, using multiomics and other complementary approaches, and (b) test the efficacy of our new California Precision Intervention for Stress and Resilience (PRECISE) in adults with elevated perceived stress levels who have experienced the full range of ACEs. The primary trial outcome is perceived stress, and the secondary outcomes span a variety of psychological, emotional, biological, and behavioral variables, as assessed using self-report measures, wearable technologies, and extensive biospecimens (i.e. DNA, saliva, blood, urine, & stool) that will be subjected to genomic, transcriptomic, proteomic, metabolomic, lipidomic, immunomic, and metagenomic/microbiome analysis. In this protocol paper, we describe the scientific gaps motivating this study as well as the sample, study design, procedures, measures, and planned analyses. Ultimately, our goal is to leverage the power of cutting-edge tools from psychology, multiomics, precision medicine, and translational bioinformatics to identify social, molecular, and immunological processes that can be targeted to reduce stress-related disease risk and enhance biopsychosocial resilience in individuals and communities worldwide.

  View details for DOI 10.1080/10253890.2024.2401788

  View details for PubMedID 39620249

• ApoA-I Nanotherapy Rescues Postischemic Vascular Maladaptation by Modulating Endothelial Cell and Macrophage Phenotypes in Type 2 Diabetic Mice Arteriosclerosis, Thrombosis, and Vascular Biology Babu, M., Devi, D., Örd, T., Aavik, E., Kaikkonen, M., Ylä-Herttuala, S. 2022

  View details for DOI 10.1161/ATVBAHA.122.318196

• Aggravated Postinfarct Heart Failure in Type 2 Diabetes Is Associated with Impaired Mitophagy and Exaggerated Inflammasome Activation AMERICAN JOURNAL OF PATHOLOGY Devi, T., Babu, M., Makinen, P., Kaikkonen, M. U., Heinaniemi, M., Laakso, H., Yla-Herttuala, E., Rieppo, L., Liimatainen, T., Naumenko, N., Tavi, P., Yla-Herttuala, S. 2017; 187 (12): 2659-2673

  Abstract

  Type 2 diabetes mellitus (T2DM) is a major risk factor for heart disease. Mortality rates after myocardial infarction (MI) are significantly increased in T2DM patients because of dysfunctional left ventricle (LV). However, molecular pathways underlying accelerated heart failure (HF) after MI in T2DM remain unclear. We investigated the underlying mechanisms by inducing MI in a well-established model of T2DM and control mice. Cardiac imaging revealed a significantly decreased global left ventricular ejection fraction in parallel with increased mortality after MI in T2DM mice compared with control mice. Genome-wide mRNA sequencing, immunoblot, electron microscopy, together with immunofluorescence staining for LC3 and p62 indicated an impaired mitophagy in peri-infarct regions of LV in T2DM mice compared with control mice. Furthermore, defective mitophagy was associated with an increased release of mitochondrial DNA, resulting in Aim2 and NLRC4 inflammasome and caspase-I hyperactivation in cardiomyocytes and cardiac macrophages in peri-infarct regions of LV in T2DM mice. Consistent with inflammasome and caspase-I hyperactivation, cardiomyocyte death and IL-18 secretion were increased in T2DM mice. Our results indicate that T2DM aggravates HF after MI through defective mitophagy, associated exaggerated inflammasome activation, cell death, and IL-18 secretion, suggesting that restoring mitophagy and inhibiting inflammasome activation may serve as novel targets for the prevention and treatment of HF in T2DM.

  View details for DOI 10.1016/j.ajpath.2017.08.023

  View details for Web of Science ID 000417009100005

  View details for PubMedID 28935571

• Differential Promoter Methylation of Macrophage Genes Is Associated With Impaired Vascular Growth in Ischemic Muscles of Hyperlipidemic and Type 2 Diabetic Mice Genome-Wide Promoter Methylation Study CIRCULATION RESEARCH Babu, M., Devi, T., Makinen, P., Kaikkonen, M., Lesch, H. P., Junttila, S., Laiho, A., Ghimire, B., Gyenesei, A., Yla-Herttuala, S. 2015; 117 (3): 289-299

  Abstract

  Hyperlipidemia and type 2 diabetes mellitus (T2DM) severely impair adaptive vascular growth responses in ischemic muscles. This is largely attributed to dysregulated gene expression, although details of the changes are unknown.To define the role of promoter methylation in adaptive vascular growth in hyperlipidemia (LDLR(-/-)ApoB(100/100)) and T2DM (IGF-II/LDLR(-/-)ApoB(100/100)) mouse models of hindlimb ischemia.Unilateral hindlimb ischemia was induced by ligating femoral artery. Perfusion was assessed using ultrasound, and capillary and arteriole parameters were assessed using immunohistochemistry. Genome-wide methylated DNA sequencing was performed with DNA isolated from ischemic muscle, tissue macrophages (Mϕs), and endothelial cells. Compared with the controls, hyperlipidemia and T2DM mice showed impaired perfusion recovery, which was associated with impaired angiogenesis and arteriogenesis. Genome-wide proximal promoter DNA methylation analysis suggested differential patterns of methylation in Mϕ genes in ischemic muscles. Classically activated M1-Mϕ gene promoters, including Cfb, Serping1, and Tnfsf15, were significantly hypomethylated, whereas alternatively activated M2-Mϕ gene promoters, including Nrp1, Cxcr4, Plxnd1, Arg1, Cdk18, and Fes, were significantly hypermethylated in Mϕs isolated from hyperlipidemia and T2DM ischemic muscles compared with controls. These results combined with mRNA expression and immunohistochemistry showed the predominance of proinflammatory M1-Mϕs, compared with anti-inflammatory and proangiogenic M2-Mϕs in hyperlipidemia and T2DM ischemic muscles.We found significant promoter hypomethylation of genes typical for proinflammatory M1-Mϕs and hypermethylation of anti-inflammatory, proangiogenic M2-Mϕ genes in hyperlipidemia and T2DM ischemic muscles. Epigenetic alterations modify Mϕ phenotype toward proinflammatory M1 as opposed to anti-inflammatory, proangiogenic, and tissue repair M2 phenotype, which may contribute to the impaired adaptive vascular growth under these pathological conditions.

  View details for DOI 10.1161/CIRCRESAHA.115.306424

  View details for Web of Science ID 000358045300010

  View details for PubMedID 26085133