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.

Bime, C., Zhou, T., Wang, T., Slepian, M. J., Garcia, J. G., & Hecker, L. (2016). Reactive oxygen species-associated molecular signature predicts survival in patients with sepsis. Pulmonary circulation, 6(2), 196-201.

Sepsis-related multiple organ dysfunction syndrome is a leading cause of death in intensive care units. There is overwhelming evidence that oxidative stress plays a significant role in the pathogenesis of sepsis-associated multiple organ failure; however, reactive oxygen species (ROS)-associated biomarkers and/or diagnostics that define mortality or predict survival in sepsis are lacking. Lung or peripheral blood gene expression analysis has gained increasing recognition as a potential prognostic and/or diagnostic tool. The objective of this study was to identify ROS-associated biomarkers predictive of survival in patients with sepsis. In-silico analyses of expression profiles allowed the identification of a 21-gene ROS-associated molecular signature that predicts survival in sepsis patients. Importantly, this signature performed well in a validation cohort consisting of sepsis patients aggregated from distinct patient populations recruited from different sites. Our signature outperforms randomly generated signatures of the same signature gene size. Our findings further validate the critical role of ROSs in the pathogenesis of sepsis and provide a novel gene signature that predicts survival in sepsis patients. These results also highlight the utility of peripheral blood molecular signatures as biomarkers for predicting mortality risk in patients with sepsis, which could facilitate the development of personalized therapies.

Ding, Q., Subramanian, I., Luckhardt, T. R., Che, P., Waghray, M., Zhao, X. K., Bone, N., Kurundkar, A. R., Hecker, L., Hu, M., Zhou, Y., Horowitz, J. C., Vittal, R., & Thannickal, V. J. (2017). Focal adhesion kinase signaling determines the fate of lung epithelial cells in response to TGF-β. American journal of physiology. Lung cellular and molecular physiology, 312(6), L926-L935.

Alveolar epithelial cell (AEC) injury and apoptosis are prominent pathological features of idiopathic pulmonary fibrosis (IPF). There is evidence of AEC plasticity in lung injury repair response and in IPF. In this report, we explore the role of focal adhesion kinase (FAK) signaling in determining the fate of lung epithelial cells in response to transforming growth factor-β1 (TGF-β1). Rat type II alveolar epithelial cells (RLE-6TN) were treated with or without TGF-β1, and the expressions of mesenchymal markers, phenotype, and function were analyzed. Pharmacological protein kinase inhibitors were utilized to screen for SMAD-dependent and -independent pathways. SMAD and FAK signaling was analyzed using siRNA knockdown, inhibitors, and expression of a mutant construct of FAK. Apoptosis was measured using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. TGF-β1 induced the acquisition of mesenchymal markers, including α-smooth muscle actin, in RLE-6TN cells and enhanced the contraction of three-dimensional collagen gels. This phenotypical transition or plasticity, epithelial-myofibroblast plasticity (EMP), is dependent on SMAD3 and FAK signaling. FAK activation was found to be dependent on ALK5/SMAD3 signaling. We observed that TGF-β1 induces both EMP and apoptosis in the same cell culture system but not in the same cell. While blockade of SMAD signaling inhibited EMP, it had a minimal effect on apoptosis; in contrast, inhibition of FAK signaling markedly shifted to an apoptotic fate. The data support that FAK activation determines whether AECs undergo EMP vs. apoptosis in response to TGF-β1 stimulation. TGF-β1-induced EMP is FAK- dependent, whereas TGF-β1-induced apoptosis is favored when FAK signaling is inhibited.

Hecker, L., Khait, L., Radnoti, D., & Birla, R. (2008). Development of a microperfusion system for the culture of bioengineered heart muscle. ASAIO journal (American Society for Artificial Internal Organs : 1992), 54(3), 284-94.

Tissue engineering strategies are being used to develop functional 3D heart muscle in vitro. Work within our own group has been focused on the development of bioengineered heart muscle using fibrin gel as a support matrix. As tissue engineering models of heart muscle are developed in the laboratory, a critical technologic challenge remains the ability to delivery nutrients to the entire tissue construct. To address this specific need, we have developed a novel perfusion system for cardiac tissue engineering applications. The system consists of a custom microincubator, designed to house ten 35-mm tissue culture plates on independent platforms for controlled fluid delivery and aspiration. Temperature, pH, and media flow rate and oxygenation are all regulated. In the current study, we describe the compatibility of this microperfusion system with bioengineered heart muscles. We demonstrate that the perfusion system is capable of supporting construct viability (mitochondrial activity, total protein, and total RNA) and maintaining contractile properties (twitch force, specific force, and electrical pacing).

Stopper, G. F., Hecker, L., Franssen, R. A., & Sessions, S. K. (2002). How trematodes cause limb deformities in amphibians. The Journal of experimental zoology, 294(3), 252-63.

We used trematode cyst infestation to induce limb deformities in two species of frogs of the genus Rana and compared them to deformities induced by surgical limb bud rotations. The specific deformities produced by both treatments closely resemble those of wild-caught deformed amphibians and are consistent with a known developmental response to disruption of the spatial organization of cells in developing limb buds. Histological analysis showed that trematode cysts cause massive disruption and abnormal cellular growth involving the limb buds of infected individuals. Our results indicate that trematode cyst infestation causes deformities in frogs by perturbation of the positional relationships of cells in developing limb buds. The crippling effects of cyst-infection on frogs may reflect complex co-evolutionary interactions among trematodes, frogs, and other hosts in the trematode's life cycle.