Dr. Judith Gault's research is investigating the characterization
of a treatment-Response biomarker in patients with schizophrenia, addressing a critical barrier to successfully treating schizophrenia; determining the optimal dose of antipsychotic medications. Schizophrenia manifests with hallucinations, delusions and paranoia making it difficult to determine what is real, leaving the person unable to care for themselves. Currently antipsychotic medication dose is titrated up to a level within a recommended range by subjective means (questioning and observing patients) and trial and error. Antipsychotics frequently do not alleviate all psychotic symptoms, making it challenging to identify an optimal dose. Each error in medication dose subjects patients to relapse, or overmedicating with increased susceptibility to unwanted side effects. Relapse and medication noncompliance are primary contributors to the burden of schizophrenia disease. Dr. Gault's research goal is to identify an objective treatment-response biomarker that could be employed to measure antipsychotic treatment success. In collaboration with psychiatrist Ann Olincy, MD and the director of Behavioral Health at Denver Health, Robert House, MD, we have identified a putative peripheral blood treatment-response biomarker with a 40% reduction in transcript levels that were associated with successful antipsychotic treatment in 92% of hospitalized patients with schizophrenia in this study (N=12). The biomarker appears promising because it was identified in patients that were heterogeneous in regard to medication, comorbid disease, age, sex ethnicity, compliance before hospitalization, drug use, smoking and homelessness. The treatment-response biomarker appears to be in a regulatory feedback loop with dopamine DRD2 and serotonin 5HT2A receptor activation. Antipsychotics are antagonists of both DRD2 and 5HT2A receptors. We are attempting to replicate these findings as part of the Challenge award and intend to learn more about the usefulness and limitations of this antipsychotic treatment-response biomarker.
Dr. Gault also collaborates with UC Denver neurosurgeons and pathologist Dr. DeMasters in investigating the genetics of stroke. Stroke is the 3rd leading cause of death in the United States and accounts for the largest portion of disability in people over the age of 60. Cerebral vascular malformations (CVMs) affect 3 million Americans, predisposing patients to a lifetime risk of hemorrhagic stroke and epilepsy. Cerebral cavernous malformation (CCM) lesions consist of dysmorphic blood filled caverns that are prone to repetitive hemorrhages and ongoing dysangiogenesis with proliferation of vascular endothelial cells to form new caverns. Familial CCM is genetically heterogeneous and families exhibit autosomal dominant Mendelian (single gene) inheritance at 3 known genes (CCM1, CCM2 and CCM3). However, within families there are clinically asymptomatic members and others with fatal disease. The CCM1, CCM2, and CCM3 genes have been identified contributing to approximately 40-54%, 13-38% and 4-6% of non-Hispanic familial cases, respectively. The majority of patients (80%) with CCM are apparently sporadic without a known family history of CCM. Single lesions are found in 75% of patients with sporadic CCM. The additional 25% of sporadic patients without a family history of disease have multiple CCMs and are thought to result from spontaneous new germline mutations or be unrecognized familial cases. Germline mutations have not been identified in sporadic CCM cases with single lesions; consistent with the hypothesis that these may result from somatic mutation(s) in the CCM genes. Our groupSomatic mutation detection in CCM lesions is technically challenging due to the fact that vascular endothelial cells that have been shown to harbor the somatic mutations comprise as little as 2.5%-10% of the cells of the lesions. Arteriovenous malformations (AVMs) of the brain and spinal cord are characterized by abnormal tangles of arteries and enlarged venous outflow channels (without an intervening capillary bed). Under high-flow conditions and arterialized pressure, AVMs are prone to catastrophic rupture. While the development of more definitive and safe treatment options for AVMs remains an issue of pressing clinical concern, basic understanding of the genetics in relation to pathobiology is an essential first step. CVM disease-causing genes have an essential, non-redundant function in angiogensis, establishing and maintaining the blood brain barrier in vascular endothelial cells. Therefore, CVM disease genes are important targets for cancer therapies.