Our laboratory focuses on understanding the genetic basis and molecular mechanisms of human disorders and aging. We are striving for EAF (E = Evolutionary analysis; A = Association study; F = Functional assay), Easy And Fun.
Major research interests
We are interested in genetic basis and molecular mechanism of human diseases. Our current research is focused on two major directions:
(1) Onset risk factors and pathogenesis of Alzheimer,s disease, schizophrenia, leprosy, and LHON;
(2) Biology of Chinese tree shrew and establishment of a tree shrew inbred strain.
Following a simple thought that diseases are some kind of traits that were either fixed in the population (hereditary diseases) or occurred in the population as an acquired character (acquired diseases), and all these processes had their unique evolutionary history, we could decipher the genetic susceptibility and mechanism from an evolutionary medicine perspective. The disease causing mutations were accumulated on DNA sequences and were subjected to selection during the long time period . Similarly, the cross-talk and interactions between genes, pathways and environment reflected the adaptation to the past environment. Alteration of the current environment may cause unfitness to this ancient adaptation, as demonstrated by the fact that ancestral alleles might lead to the risk of common diseases in Today,s population. Therefore, reconstructing the evolutionary history of the risk alleles is crucial for us to decipher the mechanism of human disorders.
We will employ the next generation sequencing technique to perform genome-wide sequencing / whole exome sequencing analysis for patients with Alzheimer,s disease, schizophrenia, leprosy and related neuropsychiatric and neurological diseases.
Why we chose to analyze these diseases is that bacterial and viral infections and subsequent inflammation, and mitochondrial dysfunction played a key role in neurodegenerative diseases. Leprosy is a chronically infectious disease and neurological disorde, and can provide essential information for us to understand the abnormal communication between the immune system and the nervous system of the body during the onset of the disease. Schizophrenia and Alzheimer,s disease are neuropsychiatric disorders, and we speculate that the immune system genes and mitochondrial genes may be actively involved in the development of these diseases. We hope that by focusing on the neuroimmunology, we may find a new window to decipher the pathogenesis of these important diseases, which cause a heavy burden to the society, families and patients.
Meanwhile, we will carry out systematic studies to functionally characterize the putative pathogenic mutations that were distilled from the genome-wide assay. By overexpressing the mutant or knockdown the expression of the target gene at the cellular level, we attempt to uncover the role of target gene and characterize the pathway / regulation network. We have established a stable system for neuron differentiation from embryonic stem cells and induced pluripotent stem cell, and will use this system to analyze these genes involved in the neurological and neuropsychiatric diseases. On the other hand, we will use mouse, tree shrew and monkey to create related disease model, and perform in vivo assay.
Mitochondria provide energy to the cell and have important roles in intracellular signaling and apoptosis and in intermediary metabolism. Most recently, studies have shown that mitochondria are also involved in antiviral responses and act as a platform for anti-pathogen signaling. Mitochondrial dysfunction causes respiratory chain defects and lead to ATP depletion, superoxide overproduction, metabolic imbalance, and disturbed signaling pathways. Clinical expression of the defects of mitochondrial function is very complex and affects a wide range of human diseases and age-related disorders. The prevalence of mitochondrial diseases is considerably high and reaches 1-1.5 in 10,000 individuals. Hitherto, the molecular basis for the majority of inherited mitochondrial disorders is still unclear. Mutations in mtDNA and nuclear gene-encoded mitochondrial proteins have been shown to be involved in their pathogenesis and disease progression. Among the list of around 1500 mitochondrial proteins (including 13 proteins encoded by mtDNA), half of them have not been fully analyzed and their exact functions are unknown. Over 100 mtDNA mutations have, to date, been confirmed to be pathogenic or associated with human diseases that present with wide-ranging clinical complications. In some cases, pathogenic expression of the homoplasmic mtDNA mutations involves complex nuclear- mitochondrial interactions, which further complicates the etiology of mitochondrial diseases. Recent studies have also indicated that mtDNA derangements and background play a role in the ensuing susceptibility to cancers and metabolic diseases of high prevalence (such as type 2 diabetes), and in the ageing process, although the original claims need to be independently verified by other groups. Experimental data from mouse model provide further insights into the necessity of mtDNA replication and maintenance during early embryo development and modified changes leading to ageing. Because of these features, studying mitochondrial dysfunction and diseases remains only of the hottest subjects in the medical field. It is conceivable that an extensive study of mutation spectra and functional characterization of the mutants identified in mitochondrial genes will help to elucidate the etiology of human mitochondrial disorders. Meanwhile, it will also help to design accurate molecular diagnostic methods and provide the scientific basis for novel therapeutical strategies for mitochondrial diseases and age-related disorders caused by mitochondrial dysfunction.