Biology subjects

Thanapaul, R. J. R. S.

Publications and source records attributed to Thanapaul, R. J. R. S..

3 recordsLinked to original sources

bioRxiv2026

Rapid Intracellular Delivery of Human Heat Shock Protein 72 Prevents Memory Loss and Inhibits Neurodegeneration up to 9 Days After a Blast Injury

Traumatic brain injuries (TBIs) are increasingly prevalent among military service members and are associated with long-term neurological impairment and neurodegeneration. Heat shock protein 72 (HSP72) has demonstrated cytoprotective properties and has been shown to cross the blood brain barrier in rat models of blast injury, remaining in brain tissue for up to 12 hours. In this study, we evaluate engineered Fv-HSP72 variants for their ability to reduce neurodegeneration and preserve short-term memory following blast-induced TBI. Male Sprague-Dawley rats were assigned to 9 groups of n = 8 rats. Animals were either not exposed to blast (Sham), exposed to blast (Blast Only), blast exposed and given buffer (Vehicle), or blast exposed and treated with one of three Fv-HSP72 variants, dosed at 10 or 30mg/kg at 15m post-blast. Blast exposure was generated using an Advanced Blast Simulator (ABS) producing positive static pressure to model moderate to severe blast injury. Animals were euthanized 48 hours post injury for neurodegeneration and immunologic biomarker analysis. After selecting an effective Fv-HSP72 variant using the biomarker data, additional rats were divided into Sham, Vehicle, and Fv-HSP72 treatment groups to evaluate short-term memory function through the Novel Object Recognition (NOR) test on days 2 and 8 post-blast. Analysis of cortical and spinal cord tissues demonstrated a statistically significant reduction in expression of neurodegenerative markers of Tau phosphorylation and glial injury (GFAP) for rats receiving a single dose of our clinical candidate, RBB012-CTB. In fact, the drug drove astrogliosis toward a neuroprotective state in blast exposed rats. In the NOR assay, Fv-HSP72 treated rats showed improved recognition performance, indicating preservation of short-term memory function. With similar biomarker results obtained for a controlled cortical impact injury model published elsewhere (Chan et al. manuscript submitted), the analyses suggest Fv-HSP72 is neuroprotective following a blast injury as well. One sentence summaryThis study describes the effectiveness of a biologic agent, Fv-HSP72, in significantly preventing learning and memory loss in rats for up to 9 days after a blast injury.

neuroscience↗

bioRxiv2025

Diminished and altered cellular senescence response in delayed wound healing of aging

The transient upregulation of cellular senescence within wound tissues has been demonstrated to be an important biological process facilitating efficient tissue repair. Dysregulation of this transient wound-induced senescence-like response can result in impaired healing outcomes. Given the established age-related decline in tissue regenerative capacity, we hypothesized that alterations in this senescence response contribute to the delayed healing of cutaneous wounds in aged individuals. Our investigation demonstrated a significant delay in the closure of full-thickness dorsal skin wounds in aged mice compared to their young counterparts. Analysis of the wound microenvironment revealed a transient upregulation of senescence-associated markers (p16, p21, senescence-associated {beta}-galactosidase) and senescence-associated secretory phenotype factors in the wound tissue of young mice, a response that was markedly attenuated in aged mice. Single-cell RNA sequencing analysis of all cells isolated from day 6 wounds identified a distinct population of p16+/p21+/Ki67- senescent fibroblasts in young mice, characterized by a transcriptional signature indicative of pro-healing extracellular matrix production, a finding corroborated in human wound tissue from young donors. Crucially, in aged wounds, we observed a lower quantity of these senescent cells, a deficit compounded by a qualitative, age-dependent shift in their function, moving away from beneficial extracellular matrix remodeling towards a more detrimental pro-inflammatory state, which ultimately can contribute to the delayed wound healing.

cell biology↗

bioRxiv2024

Topical ABT-1 263 treatment reduces aged skin senescence and improves subsequent wound healing

Senescent cells (SnC) accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating SnC skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period. Following topical ABT-263, aged skin demonstrated decreased gene expression of senescent markers p16 and p21, accompanied by reductions in SA-{beta}-gal and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.

cell biology↗