■ Research interest
Specific Research Topics under Current Investigation
Schizophrenia consists of various different symptoms. Although various
treatments for schizophrenia have been developed, it is unclear how a particular
treatment will affect a specific patient. Our lab is using blood profiling
to classify schizophrenic patients into different subgroups in order to
develop novel targeted treatments. In particular, we are analyzing differences
in markers of carbonyl stress (CS), oxidative stress (OS), and advanced
glycation end products (AGEs) between control and schizophrenic patients
to more accurately characterize the disease. Developing metabolic profiles
from the blood of schizophrenic patients will allow us to diagnose the
disease earlier, elucidate the molecular mechanisms involved in the disease,
and develop appropriate treatments and prophylactic methods.
We have found that a subclass of treatment-resistant schizophrenia patients show depletions in vitamin B6, increases in CS, and accumulation of pentosidine and AGEs (Arai et al., Arch Gen Psychiatry. 2010; Miyashita et al., Schizophr Bull. 2014; Arai et al., Psychiatry Clin Neurosci. 2014). This suggests that this subclass of patients may respond well to treatments increasing vitamin B6. Using similar strategies, we plan to modify patient treatment from a general disease-based approach to a tailored individual-based approach. We are currently consolidating data from (1) metabolic studies, (2) genome analyses, (3) induced pluripotent stem (iPS) cell models, (4) animal models, and (5) post-mortem brains to build a database of basic and clinical findings on schizophrenia. This database will allow us to characterize different subclasses of the disease, understand the molecular bases of onset and pathology of these subclasses, elucidate the genetic and environmental factors influencing these subclasses, and develop specific treatment strategies for each subclass.
Purpose of research
Our aim is to build a database of basic and clinical data by compiling findings obtained from genome and biomarker studies, metabolic research, and case studies. Pathological hypotheses obtained from basic research will be verified using post-mortem brain studies, and cellular, and animal models. From these studies, we will identify candidate molecules for drug development. Our goal is to improve the quality of life (QOL), improve cognitive function, and reduce negative symptoms associated with schizophrenia. We are focusing on the four following strategies.
1) Research using human clinical specimens:
The aim is to identify biomarkers useful in objectively diagnosing psychiatric disorders, including schizophrenia, while avoiding confounding results caused by heterogeneity of these disorders. CS, OS, and AGE markers in clinical specimens will be analyzed by mass spectrometry. To date, we have collected approximately 500-1,000 specimens, primarily from patients with schizophrenia, and we are continuing to develop a database of biomarkers. We are also collecting and analyzing specimen from patients with bipolar disorder and depression. We expect to identify biomarkers useful for early diagnosis of psychiatric disorders, including schizophrenia.
2) Research using iPS cell models:
We are generating iPS cells from patients with schizophrenia and healthy individuals, and differentiating these cells into neurons and glial cells. We are analyzing these cells to identify molecular differences associated with schizophrenia.
3) Research using human post-mortem brains:
Schizophrenia is associated with increases in CS, OS, and AGEs, including pentosidine. However, brain locations where these products accumulate have not been systematically studied. We will identify the histopathology of CS, OS, and AGEs in post-mortem brain tissue using specific antibodies. This will allow us to elucidate the relationship between clinical symptoms and accumulation of stress markers and glycation end products in specific brain areas.
4) Research using mouse models:
We will analyze a glo1 knockout mice model for schizophrenia. We will characterize the relationship between mouse behavioral changes with various metabolisms. We will further identify drug compounds that improve symptoms and cognitive deficits associated with this mouse model.
Expected results and impactsAnalyzing changes in CS, OS, and AGEs associated with schizophrenia is a novel research strategy that will lead to development of safer treatments and prophylactic methods. CS, OS, and AGEs can be measured in blood samples facilitating the early characterization, diagnosis, and treatment of the disease. We hope our work contributes to the development of novel treatments for schizophrenia and improvements in the QOL of patients.
Schizophrenia Research Project, Project Leader,
Deputy Associate Director,
Makoto ARAI Ph.D.