Neuropathology

Research Description

Mechanisms Underlying Glioblastoma Progression
We investigate mechanisms of progression to glioblastoma (GBM), the highest grade astrocytoma, including genetics, hypoxia, and angiogenesis. Progression is characterized by tumor necrosis, severe hypoxia and microvascular hyperplasia, a type of angiogenesis. We propose that vaso-occlusion and intravascular thrombosis within a high grade glioma results in hypoxia, necrosis and hypoxia-induced microvascular hyperplasia in the tumor periphery, leading to neoplastic expansion outward. Since the pro-thrombotic protein tissue factor is upregulated in gliomas, we investigate mechanisms of increased expression and pro-coagulant effects.

In Silico Brain Tumor Research
We initiated an In Silico Center for Brain Tumor Research to investigate the molecular correlates of pathologic, radiologic and clinical features of gliomas using pre-existing databases, including as TCGA and Rembrandt. Using datasets and image analysis algorithms, we study whether elements of the tumor micro-environment, such as tumor necrosis, angiogenesis, inflammatory infiltrates and thrombosis, may correlate with gene expression subtypes in TCGA gliomas. We also have demonstrated the clinical relevance of TCGA subclasses within the lower grade gliomas using the Rembrandt dataset.

Regulators of Asymmetric Cellular Division in Glioblastoma Stem Cells
We study mechanisms that confer specialized biologic properties to glioma stem cells (GSC) in GBM. The Drosophila brain tumor (brat) gene normally regulates asymmetric cellular division and neural progenitor differentiation in the CNS of flies and, when mutated, leads to a massive brain containing only neuroblastic cells with tumor-like properties. We study the human homolog of Drosophila brat, Trim3, for its role in regulating asymmetric cell division and stem-like properties in GSCs. Trim3 may elicit its effects is through repression of c-Myc.

For more information, visit the faculty profile of Daniel Brat, MD, PhD or the Brat Lab website.

Publications

See Dr. Brat's publications in PubMed.

Contact

Email Dr. Brat

Our lab is dedicated to understanding the impact of senescent microglia on Alzheimer’s disease (AD) and Parkinson’s disease (PD) using genetic mouse models and cell culture systems. Aging, the primary risk factor for these neurodegenerative diseases, results in the accumulation of senescent cells in the brain. These cells, often referred to as “zombie” cells, are characterized by irreversible cell cycle arrest and distinct phenotypic changes, including increased levels of cell-cycle inhibitors, heightened senescence-associated β-galactosidase activity, and the senescence-associated secretory phenotype (SASP). These cells can persist in tissues and chronically damage their environment through pro-inflammatory factors, potentially leading to the loss of neuroprotective functions and increased brain inflammation. Our research objectives include:
1. Determining how disease conditions promote microglial senescence
2. Identifying the mechanisms that link senescent microglia to neurotoxicity
3. Examining the influence of genetic risk factors on these pathways
We aim to uncover critical insights into microglial senescence and its implications for neurodegenerative diseases by employing reporter mouse lines to detect senescent cells in AD and PD models. This research could potentially reveal new therapeutic targets and enhance our understanding of age-related neurological disorders.

For more information, please visit the Choi Laboratory website.