Overall Research Objective:
Our research is focused on studying genes and mechanisms involved in intermittent and constant hypoxia injury/ adaptation using Drosophila as the model system. This research can further be translated into mice and other vertebrate models and have relevance in understanding mechanisms involved in ailments such as sleep apnea, asthma and sickle cell anemia.
Determining the Role of Hypoxia and Hypercapnia in Cardiovascular Disease
Obstructive sleep apnea (OSA), which may affect up to 4% of males and 2% of females, has been shown to induce cardiovascular morbidity and contribute to the pathogenesis of cardiovascular diseases including hypertension, heart failure, ischemic heart disease and atherosclerosis. Alternating periods of normoxia and hypoxia (intermittent hypoxia; IH), as well as intermittent hypercapnia (IC), have been demonstrated in several disease states, such as OSA. My (our) laboratory focuses on the determination of the role of intermittent hypoxia (IH) and intermittent hypercapnia (IC) or the combination thereof (IHH) in the progression of atherosclerotic plaque development in mouse models that are genetically prone to atherosclerosis. Since inflammation is a critical component of atherosclerotic progression, we also focus on the response of the immune system to intermittent hypoxia and intermittent hypercapnia. Therefore, we utilize a variety of histological and molecular biology techniques to determine the mechanisms that underlie the pathology induced by sleep disordered breathing.
Cell-Signaling Pathways of Cardiovascular Disease
Our research interests are to understand the molecular mechanism of cardiovascular diseases by utilizing genetically engineered mouse models, combined with physiological, molecular and cell biological techniques. The ultimate goal is to identify potential therapeutic targets for cardiovascular diseases.
Chronic Pulmonary Acidosis and Diabetes
We use electrophysiological and ELISA methods to explore the cellular and molecular mechanism of the pulmonary acidosis in relation to glucose-stimulated insulin release in diabetes. Our ultimate goal is to find a way to alleviate the pain of diabetes patients with chronic diseases such as COPD, obstructive sleep apnea.
Hypoxia Effect on Glioblastoma LN229 Cells
Glioblastomas are the most common malignant brain tumor in adults, and also the most resistant of all cancers to treatment. Our research showed that unlike regular plasma membrane, which responds to hypoxia by reducing its BK channel activity, the inner membrane from glioblastoma mitochondria responded to hypoxia by increasing its BK channel activity, such as the open probability. Our research goal is to seek the mechanism of tumor metastasis using a tumor cell line as a model.
Role of Drosophila dMRP4 in Hypoxia Tolerance on Immune Pathways
We are exploring the genetic basis for cells or animals to sense and respond to hypoxia (low oxygen) using Drosophila, one of a few species capable of tolerating very low oxygen environment as a model animal. We took a reverse genetic approach to screen genes whose mis-expression caused abnormal behavioral response to oxygen deprivation. Of more than 1600 EP lines screened, one gene product whose mis-expression was found to be particularly sensitive hypoxia, namely dMRP4, a homolog of human MRP4 (multidrug resistance-associated protein 4, also known as ABCC4). Ongoing work now is to study mechanisms as to why and how a drug transporter involves regulation of hypoxia response in Drosophila.
Huang He, Ph.D.
Genetic Mechanisms Underlying Obesity and Hypoxia
Over 60% of the US population is estimated to be obese or overweight, a number that has dramatically increased in recent decades and continues to climb. With obesity come many disease complications, several of which also involve hypoxia, including atherosclerosis, stroke, asthma and sleep apnea. Using a Drosophila model, we have characterized the phenotypic changes that occur with obesity and hypoxia, both as separate challenges and interacting factors. We are working to uncover the genetic mechanisms underlying the altered phenotype due to obesity and hypoxia.
Chronic Hypercapnia Effects on the Immune System
Hypercapnia (high carbon dioxide levels in blood or tissue) is a state that is common in many lung diseases such as bronchopulmonary dysplasia and asthma. We are currently studying the effect of hypercapnia during lung development. Our studies have found that mice exposed to high carbon dioxide levels during lung development have altered lung function and lung matrix composition. In addition, our data suggest that hypercapnia may alter immune function and thus may impair bacterial clearance during lung infections.
Notch Signaling Pathway of Hypoxia
We are working on understanding the interactions between the Notch signaling pathway and hypoxia. We are studying why Up-regulation of the Notch signaling pathway in glia cells in the Drosophila brain leads to survival during chronic hypoxia.
Genetic Mechanisms Underlying Ischemic Infarct Expansion
Studies from both stroke patients and animal stroke models have demonstrated that Ischemic infarct expansion following stroke exacerbates neurologic outcome. Our research interest has been focused on understanding the mechanisms underlying infarct expansion. In the past several years, we have developed an in vitro model that simulates the cell death in the ischemic penumbra (peri-infarct region in focal ischemic brain, cell death in this region accounts for the infarct expansion). We have used this model together with an in vivo mouse stroke model to study the potential role of several genes (that were found up-regulated by microarray analysis using the above in vitro model) in the ischemic infarct expansion.
Mechanisms Underlying Hyperoxia Tolerance
Our research interest focuses on oxidative stress and injury, especially in hyperoxia-induced oxidative stress. We are currently working on investigating the potential genes and pathways underlying hyperoxia tolerance using Drosophila as a model system.
Genetic Basis of Tolerance and Susceptibility to Hypoxia
Our research projects are aimed at understanding the mechanisms underlying adaptation and injury in hypoxic and hyperoxic environments. Drosophila model, mouse model and a combination of genetic, genomic and molecular biology tools are used to conduct research. In the past several years, we have generated Drosophila models that tolerate extremely low or high O2 conditions. Currently, we are using these powerful models to dissect genes and pathways that regulate adaptive or injury response to hypoxic or hyperoxic stimuli.
Dan Zhou, Ph.D.