Many diseases in humans are associated with dysregulation of cell death and survival. Excessive cell death, via apoptosis, necroptosis, or other forms of cell death, leads to loss of functional cells and is linked to disease conditions such as to myocardial infarction, stroke, neurodegenerative disorders, renal failure, and diabetic complications. On the other hand, aberrant repression of cell death may be causally linked to tumorigenesis (cancers), autoimmune diseases, and productive viral infection.
- M.D. Hebei Medical College, China.
- M.S. Military Medical University, Chongqing, China.
- Ph.D. PLA General Hospital, Beijing, China.
- Postdoctoral Scholar: The University of Kentucky, Lexington, Kentucky, USA.
Current research in our laboratory centers on some of the fundamental questions in the life and death of cells in a variety of organ systems and diseases.
First, we examine how specific genetic mutations and cell death proteins regulate intracellular pathways that control neuronal life and death associated with neurodegenerative diseases. In this respect, we are specifically looking at the pathogenic mechanisms of presenilin-1 (PS-1) mutations and pro-apoptotic actions of prostate apoptosis response-4 (Par-4) protein in several transgenic mouse models of Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Mutations in presenilins-1 are responsible for the majority of early onset familial AD cases, while elevated levels of Par-4 expression are associated with increased vulnerability of neurons to apoptosis.
Available evidence also suggests that the retina may be used as a window to study neurodegeneration in Alzheimer’s disease (AD). Peroxisome proliferator activated receptor alpha (PPAR-α) is a member of ligand-regulated nuclear receptors (PPARs). Of importance, PPAR-α regulates expression of genes coding enzymes engaged in Alzheimer’s amyloid precursor protein (APP) metabolism. In AD brain expression of genes of PPAR-α and PPAR-γ coactivator-1 alpha (PGC-1α) is significantly decreased. We have identified AATF (apoptosis antagonizing transcription factor) as a neuroprotective protein. Both PPAR-α and AATF are nuclear transcription proteins involved in neuroprotection. Using the triple-transgenic mouse model of AD (3×Tg-AD) that expresses three major genes associated with familial AD, namely APPswe, PS1M146V, and tauP301L, we will test the hypothesis that AATF interacts with PPAR-α and forms a transcription complex to activate neuroprotective transcriptions in the nucleus of retinal neurons, and that a decrease/loss in PPAR-α activation and function in retinal ganglion cells (and potentially in other retinal cells including photoreceptors and bipolar cells, etc.) is an early indicator of neuronal degeneration in AD. We will also investigate if targeted delivery of small AATF core peptides across the blood-retinal barrier translates into a viable therapy for retinal degeneration in AD.
Work in Dr. Guo's lab has contributed to our understanding of a number of mechanisms for dementia of Alzheimer's type caused by the heritable alterations of genetic information in presenilin proteins, which included the investigation of neuronal cell death process in the first mouse "knock-in" model of a naturally occurring presenilin-1 mutation responsible for an early-onset form of Alzheimer disease. We also study the mechanisms by which specific proteins regulate cholinergic neurotransmission and synaptic function.
Secondly, we have recently expanded our study to include the mechanisms by which specific cell death and/or survival proteins regulate apoptosis in models of human diseases outside the central nervous system.
Specifically, we are looking at how aberrant regulation of the apoptotic machinery is involved in pathological conditions such as acute renal failure induced by ischemia/reperfusion, diabetes, cardiovascular problems, bone disease, and cancer. One of the factors we are currently working on is apoptosis antagonizing transcription factor (AATF), a novel leucine zipper protein that interacts directly with Par-4 and functions as an endogenous antagonist of Par-4 activity in many physiological and pathological settings.
Our studies involve the application of a variety of gene transfer, targeting and expression techniques, including those in applied in vitro in cultured cells and in vivo in transgenic and/or knock-in mouse models. The overall goal of our research is to understand the molecular and cellular mechanisms of cell death in human diseases, and to identify novel therapeutic strategies using genetic and/or pharmacological manipulations.
Specific areas of investigation include the following:
Regulation of apoptotic and cell survival signaling pathways by presenilin mutations
Pro-apoptotic actions of Par-4 in experimental models of neurodegenerative disorders (Alzheimer's disease and ALS)
Involvement of Par-4 in regulation of synaptic signaling and plasticity
AATF as an endogenous interaction partner and antagonist of Par-4 activity
Regulation of APP processing by Par-4 and AATF under apoptotic and non-apoptotic conditions
Roles of oxidative stress and intracellular calcium homeostasis in neurodegeneration
Par-4, AATF and pathogenesis of acute renal failure induced by ischemia/reperfusion
Novel biomarkers of retinal degeneration in models of Alzheimer’s disease
Cell death and visceral dysfunction
Research in our lab has been supported by grants from National Institutes of Health (NIH/NINDS, NIH/NIDDK), The Alzheimer's Association, The ALS Association, The American Federation for Aging Research, OCAST, Harold Hamm Diabetes Center, and the Department of Physiology at OUHSC.
- Qing Guo, Jun Xie, and Chelsea J. Guo. Par-4 in Neuronal Death and Survival in Alzheimer’s Disease and Other Neurogenerative Diseases. In (Vivek. M. Rangnekar Eds) Tumor Suppressor Par-4: Role in Cancer and Other Diseases. Vol.2 Springer Nature. 2021; 215-245.
- Jun Xie, Sima Asfa, Annalisa Manning, and Qing Guo. Inhibition of RIPK3/MLKL-dependent Necroptosis by SAP-12 in Ischemic Brain. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019; 39: 426.
- Qing Guo. New Evidence Links Calcium-Regulated Activation of Mitochondrial AGC1 to Autism. Cell Science Reviews 2010; 6(4): 24-29.
- Najeeb A Shiwany, Jun Xie and Qing Guo. Cortical neurons transgenic for human Aβ40 or Aβ42 have similar vulnerability to apoptosis despite their different amyloidogenic properties. Int J Clin Exp Pathol 2(4); 2009; 339-352.