Louise Hecker
Associate Professor, BIO5 Institute
Associate Professor, Clinical Translational Sciences
Associate Professor, Medicine
Primary Department
Department Affiliations
(520) 626-2855
Work Summary
Louise Hecker’s research is focused on understanding why the process of regenerative biology and mechanisms of tissue injury-repair "goes awry" in aging. She is working to identifying novel pathways that can be targeted to reverse age-associated diseases, such as Idiopathic pulmonary fibrosis (IPF).
Research Interest
Dr. Hecker's research background and training are rooted in regenerative biology and investigating mechanisms of tissue injury-repair. Regenerative biology studies the molecular and cellular processes by which tissues and organs renew or repair themselves. However, the normal healing and repair process becomes less efficient as we age. Dr. Hecker’s research is focused on understanding why this process "goes awry" in aging and identifying novel pathways that can be targeted to reverse age-associated diseases, such as Idiopathic pulmonary fibrosis (IPF). Research by Dr. Hecker and her colleagues at UAB identified a novel role for NADPH oxidase-4, or Nox4, an oxidant-generating enzyme that plays a critical role in the formation of scar tissue (fibrosis) in the lung (results were published in Nature Medicine in 2009). Dr. Hecker’s ongoing research involves discovering new drug candidates to target Nox4 and preclinical testing of novel therapies aimed to treat IPF. She is founder and chief scientific officer of Regenerative Solutions, LLC, a contract research organization that provides highly specialized preclinical testing services for biotechnology and pharmaceutical companies with drug development platforms in pulmonary fibrosis. She is principal investigator on a study, “Aging, Fibroblast Senescence, and Apoptosis in Lung Fibrosis,” funded through June 2017 by a nearly $1 million grant from the Department of Veterans Affairs (1 IK2 BX001477-01A1).

Publications

Hecker, L., Garcia, J. G., Wang, T., Colson, B., Knox, A., Mohamed, M., Quijada, H., Desai, A., Ahmad, K., Shin, Y. J., & Palumbo, S. (2017). Dysregulated Nox4 ubiquitination contributes to redox imbalance and age-related severity of acute lung injury. American journal of physiology. Lung cellular and molecular physiology, 312(3), L297-L308.
BIO5 Collaborators
Joe GN Garcia, Louise Hecker

Acute respiratory distress syndrome (ARDS) is a devastating critical illness disproportionately affecting the elderly population, with both higher incidence and mortality. The integrity of the lung endothelial cell (EC) monolayer is critical for preservation of lung function. However, mechanisms mediating EC barrier regulation in the context of aging remain unclear. We assessed the severity of acute lung injury (ALI) in young (2 mo) and aged (18 mo) mice using a two-hit preclinical model. Compared with young cohorts, aged mice exhibited increased ALI severity, with greater vascular permeability characterized by elevated albumin influx and levels of bronchoalveolar lavage (BAL) cells (neutrophils) and protein. Aged/injured mice also demonstrated elevated levels of reactive oxygen species (ROS) in the BAL, which was associated with upregulation of the ROS-generating enzyme, Nox4. We evaluated the role of aging in human lung EC barrier regulation utilizing a cellular model of replicative senescence. Senescent EC populations were defined by increases in β-galactosidase activity and p16 levels. In response to lipopolysaccharide (LPS) challenge, senescent ECs demonstrate exacerbated permeability responses compared with control "young" ECs. LPS challenge led to a rapid induction of Nox4 expression in both control and senescent ECs, which was posttranslationally mediated via the proteasome/ubiquitin system. However, senescent ECs demonstrated deficient Nox4 ubiquitination, resulting in sustained expression of Nox4 and alterations in cellular redox homeostasis. Pharmacological inhibition of Nox4 in senescent ECs reduced LPS-induced alterations in permeability. These studies provide insight into the roles of Nox4/senescence in EC barrier responses and offer a mechanistic link to the increased incidence and mortality of ARDS associated with aging.

Hecker, L., Murphy, K., Naomi, L., & Stanley, S. (2014). Secreted factor(s) from young cells restores suscep- tibility to cell death in senescent myofibroblasts. BioOne, 85(4), 218-223.
Sanders, Y. Y., Liu, H., Zhang, X., Hecker, L., Bernard, K., Desai, L., Liu, G., & Thannickal, V. J. (2013). Histone modifications in senescence-associated resistance to apoptosis by oxidative stress. Redox biology, 1, 8-16.

Aging and age-related diseases are associated with cellular senescence that results in variable apoptosis susceptibility to oxidative stress. Although fibroblast senescence has been associated with apoptosis resistance, mechanisms for this have not been well defined. In this report, we studied epigenetic mechanisms involving histone modifications that confer apoptosis resistance to senescent human diploid fibroblasts (HDFs). HDFs that undergo replicative senescence display typical morphological features, express senescence-associated β-galactosidase, and increased levels of the tumor suppressor genes, p16, p21, and caveolin-1. Senescent HDFs are more resistant to oxidative stress (exogenous H2O2)-induced apoptosis in comparison to non-senescent (control) HDFs; this is associated with constitutively high levels of the anti-apoptotic gene, Bcl-2, and low expression of the pro-apoptotic gene, Bax. Cellular senescence is characterized by global increases in H4K20 trimethylation and decreases in H4K16 acetylation in association with increased activity of Suv420h2 histone methyltransferase (which targets H4K20), decreased activity of the histone acetyltransferase, Mof (which targets H4K16), as well as decreased total histone acetyltransferase activity. In contrast to Bax gene, chromatin immunoprecipitation studies demonstrate marked enrichment of the Bcl-2 gene with H4K16Ac, and depletion with H4K20Me3, predicting active transcription of this gene in senescent HDFs. These data indicate that both global and locus-specific histone modifications of chromatin regulate altered Bcl-2:Bax gene expression in senescent fibroblasts, contributing to its apoptosis-resistant phenotype.

Hecker, L., Logsdon, N. J., Kurundkar, D., Kurundkar, A., Bernard, K., Hock, T., Meldrum, E., Sanders, Y. Y., & Thannickal, V. J. (2014). Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Science translational medicine, 6(231), 231ra47.

The incidence and prevalence of pathological fibrosis increase with advancing age, although mechanisms for this association are unclear. We assessed the capacity for repair of lung injury in young (2 months) and aged (18 months) mice. Whereas the severity of fibrosis was not different between these groups, aged mice demonstrated an impaired capacity for fibrosis resolution. Persistent fibrosis in lungs of aged mice was characterized by the accumulation of senescent and apoptosis-resistant myofibroblasts. These cellular phenotypes were sustained by alterations in cellular redox homeostasis resulting from elevated expression of the reactive oxygen species-generating enzyme Nox4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-4] and an impaired capacity to induce the Nrf2 (NFE2-related factor 2) antioxidant response. Lung tissues from human subjects with idiopathic pulmonary fibrosis (IPF), a progressive and fatal lung disease, also demonstrated this Nox4-Nrf2 imbalance. Nox4 mediated senescence and apoptosis resistance in IPF fibroblasts. Genetic and pharmacological targeting of Nox4 in aged mice with established fibrosis attenuated the senescent, antiapoptotic myofibroblast phenotype and led to a reversal of persistent fibrosis. These studies suggest that loss of cellular redox homeostasis promotes profibrotic myofibroblast phenotypes that result in persistent fibrosis associated with aging. Our studies suggest that restoration of Nox4-Nrf2 redox balance in myofibroblasts may be a therapeutic strategy in age-associated fibrotic disorders, potentially able to resolve persistent fibrosis or even reverse its progression.

Hecker, L. (2016). Quantitative Analyses of microRNA and Protein-Coding Gene Expression in Idiopathic Pulmonary Fibrosis Yields Novel Biomarker Signatures Predicting Survival.. NA.

Zhou, T., Sweiss, N., Ma, S., Noth, I., Hecker L, Lussier, Y. A., Garcia, J. G.N. Quantitative Analyses of microRNA and Protein-Coding Gene Expression in Idiopathic Pulmonary Fibrosis Yields Novel Biomarker Signatures Predicting Survival. In Press.