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Genomic Studies and iPSC-Based Modeling for Neurological Disorders
Genomic Studies and iPSC-Based Modeling for Neurological Disorders
Movement disorders, including Wilson’s disease (WD), Parkinson’s disease, and dystonia, arise from functional abnormalities in the basal ganglia, resulting in either hyperkinetic or hypokinetic movement patterns. As part of the "Indian Collaborative Research Network on Wilson’s Disease (iCROWD)," we have established a nationwide network comprising over 40 clinicians across 20 centers to investigate the genetic foundations of these disorders. Our research has explored the genomic landscape of Wilson’s disease using a comprehensive Pan-India disease cohort and population-scale data, leading to the development of one of the largest databases for WD.
To further uncover the molecular mechanisms of these disorders, we employ induced pluripotent stem cells (iPSCs) and organoid cultures in our laboratory. Blood samples from healthy individuals and affected patients are reprogrammed into iPSCs and differentiated into key brain cell types, such as motor neurons, astrocytes, and microglia. Using genome editing, we generate isogenic cell lines to study disease phenotypes and assess genetic variants. These advanced models serve as critical tools for understanding the pathophysiology of movement disorders and enable the identification and testing of therapeutic candidates, including repurposed drugs and protein kinase inhibitors.
Cross-talk between differentially regulated protein kinases in type 2 Diabetes Mellitus and Alzheimer's disease: Cognition and synaptic plasticity in diabetes mellitus
Cross-talk between differentially regulated protein kinases in type 2 Diabetes Mellitus and Alzheimer's disease: Cognition and synaptic plasticity in diabetes mellitus
Type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD) are both age-related conditions and their prevalence is on the rise in populations worldwide. Interestingly, AD is occasionally referred to as "type III diabetes" due to the shared risk factors between these two disorders. This connection arises from the fact that insulin plays a crucial role not only in maintaining normal brain function but also in regulating peripheral glucose metabolism. Disruptions in insulin regulation have adverse effects on both brain function and glucose control throughout the body. Various epidemiological studies have pointed to insulin resistance, a condition marked by inefficient glucose utilization, as a factor contributing to a roughly two to three-fold increase in the relative risk of developing AD.Several factors can help explain this association, including the activity of insulin-degrading enzyme (IDE), mitochondrial dysfunction, inflammation, and oxidative stress. While our understanding of the underlying causes of these two diseases remains somewhat limited, the shared pathological changes observed in their affected cell types, such as insulin-producing beta cells in diabetes and neurons in Alzheimer's disease, have led to the discovery of a new signaling pathway in pancreatic beta cells.
Cyclin-dependent kinase-5 (CDK5) and its activator p35, originally believed to be exclusive to brain tissue, have also been identified in pancreatic beta cells. In Alzheimer's patients, neuronal dysfunction has been linked to the hyperaction of CDK5/p25. Notably, both of these proteins are expressed in the insulin-producing beta cells found in the pancreas.
Our research is geared toward unraveling the specific neural circuits and molecular pathways primarily affected in the neurodegeneration associated with Type 2 Diabetes. Additionally, we aim to explore how these processes can be restored. Presently, we are actively investigating the potential role of CDK5 in cognition and synaptic plasticity in individuals with diabetes mellitus. This work holds promise for shedding light on the intricate interplay between these two complex conditions and uncovering avenues for potential therapeutic interventions.
To achieve these goals, our research employs a combination of cutting-edge technologies, including Next Generation Sequencing (NGS), human iPSCs generation, genome editing, specific cell type differentiation, brain and liver-specific 3-D organoids generation, disease-specific mouse models (eg;db/db) as well as molecular biology, biochemistry, molecular/cellular imaging, bioinformatics and neurobehavioral studies. It is our hope that our studies will bring novel mechanistic insight into these disorders and provide new therapeutic strategies for these devastating diseases that affect millions of people worldwide.
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