Characterizing the role of CARHSP1 in the aging brain and alzheimer's disease

The National Institute on Aging awarded Baylor College of Medicine $101,052 under the Aging Research program (CFDA 93.866) on December 25, 2026, to characterize the role of CARHSP1 (calcium-regulated heat stable protein 1) in the aging brain and Alzheimer's disease.

The funded research will define the role of CARHSP1 and its Drosophila homolog CG9705 in normal neuronal function through loss- and gain-of-function modeling; identify genetic interactions that mediate CARHSP1-induced toxicity by testing known disease-associated pathways; and assess whether CARHSP1 loss mitigates Alzheimer's disease progression in mammalian models using tau pathology and inflammatory markers. The work will establish CARHSP1 as a potential therapeutic target for neurodegeneration and include structured training in neurogenetics and disease modeling.

The award is a project grant with a period of performance from December 25, 2026, through July 31, 2029. Work is performed in Houston, Texas. Baylor College of Medicine, headquartered in Houston and a private non-profit research-intensive academic health sciences institution, serves as the recipient.

Abstract

Despite extensive genetic and proteomic studies in alzheimer's disease (ad), the functional impact of disease- associated variants remains poorly understood. Proteome-wide association studies (pwas) have identified variants in calcium-regulated heat stable protein 1 (CARHSP1) that are significantly associated with ad. Furthermore, even outside of these mutations, increased CARHSP1 protein and RNA levels are observed in ad brains, indicating wide-spread dysregulation in disease. CARHSP1 is an RNA-binding protein that localizes to stress granules and interacts with inflammatory and metabolic pathways. However, its role in neuronal function and neurodegeneration remains undefined. In drosophila, loss of CARHSP1 homolog, CG9705, alters synaptic activity and dendritic morphology. These findings indicate that CG9705 is required for normal neuronal function, independent of pathological stressors. Furthermore, CG9705 knockdown in tauopathy models ameliorates neurodegenerative phenotypes, while CARHSP1 overexpression exacerbates TAU-induced neurotoxicity, suggesting that CARHSP1 plays a pathogenic role in ad. I hypothesize that CARHSP1 overexpression exacerbates TAU-mediated neurotoxicity through dysregulated stress responses. To test this, aim 1 will define the role of CARHSP1/CG9705 in normal neuronal function by characterizing phenotypes in loss- and gain-of-function drosophila models. Aim 2 will identify genetic interactions that mediate CARHSP1-induced toxicity by testing known CARHSP1-associated pathways. Aim 3 will assess whether CARHSP1 loss mitigates ad progression in mammalian models using TAU pathology and inflammatory markers. These studies will provide critical insight into RNA-binding proteins in neurodegeneration and establish CARHSP1 as a potential therapeutic target. This research, combined with structured training in neurogenetics and disease modeling, will equip me with expertise to bridge basic neuroscience with clinical translation as a physician scientist studying neurodegenerative disease.