COBRE Pilot Project Program

The overall mission of the Pilot Project Program is to further solidify and enrich the pilot project program’s success achieved during Phase I and II of the COBRE by selecting talented mentees and highly experienced mentors with matching expertise and by providing a competent and effective administrative structure to guarantee good management, integration, and oversight of our pilot project core. This will be achieved by our team of COBRE director, project coordinators, senior mentors, core leaders, other steering committee members, and external advisory committee members. The success of their efforts will be assisted by our COBRE program administrator. This team of investigators and administrators provides a carefully designed framework to support and nurture our pilot project awardees and to ensure responsible conduct and scientific rigor and reproducibility of their research, as they are coached in their development as independent researchers. This supportive environment is created by providing the clear and rigorous selection process of awardees and mentors, by ensuring the formative and summative evaluation of the progress of the selected faculty, by instituting internal and external oversight of the pilot project program, and by the overt communication of the expectations placed upon both the awardees and mentors. The goal of these administrative and scientific efforts is to ensure high rate of our trainees obtaining their own significant independent funding. 

Dr. Prerna Kumar 

Kidneys are among the fastest aging organs with irreversible physiological changes that resemble chronic kidney disease (CKD). Biological sex plays a role in the development and progression of CKD, with males experiencing a faster decline in kidney function compared to females. Tubulointerstitial fibrosis and inflammation are the common mechanisms involved in the progression of CKD, which are controlled by various posttranscriptional and posttranslational modifications driven by epigenetic modifiers and small non-coding microRNAs (miRs). Epigenetic regulators including miRs have been linked to the progression and outcomes of renal injury in aging. However, epigenetic programming involved in the development of observed sex differences in age-related renal injury remains incompletely understood. Therefore, further research is needed to identify new mechanisms/ therapeutic targets to aid in designing sex-specific targeted approaches for prevention/treatment of CKD. Recently we have shown age and sex differentially regulate renal metabolism, epigenetic modifiers, and injury markers in mice, which establishes association between metabolomics and epigenetics in the progression of renal injury and inflammation. In the current study we aim to identify novel miR-133b-targets implicated in renal injury and therapeutic potential of miR-133b in reversing aging renal pathology via remodeling of epigenome. Our ongoing study has shown significant decrease in renal miR-133b expression in aged male mice compared with young male mice by real time PCR assay. Bulk RNA seq results have shown differential expression of genes in young and aged mice with sex differences. Assay for Transposase-Accessible Chromatin (ATAC-Seq) analysis will be used to elucidate age-mediated changes in renal epigenome. High throughput proteomics assay will be used to elucidate proteins that are differentially regulated in young and aged mice kidneys including epigenetic modifiers. This will help in identification of proteins which are implicated in aging renal injury as well as identification of novel epigenetic regulators of aging kidney. Our results will help in identification of novel miR-133 targets, including proinflammatory/fibrotic genes and epigenetic modifiers involved in the pathogenesis of renal aging. 

Dr. Santosh Yadav 

The pilot project focuses on investigating the role of the DNA repair protein XRCC2 in CD8+ T cell dysfunction in fibrosis, particularly in Idiopathic Pulmonary Fibrosis (IPF). The research aims to determine whether loss of XRCC2 leads to an exhaustion-like phenotype in CD8+ T cells, impairing immune surveillance and tissue regeneration. Additionally, the project explores whether reconstituting XRCC2 can restore T cell function and alleviate pulmonary fibrosis using a gene therapy approach with extracellular vesicles to enhance T cell effectiveness and promote lung regeneration. The key challenge being addressed is the hypothesis that silencing XRCC2, a regulator of homologous DNA repair, increases CD8+ T cell exhaustion, marked by the upregulation of exhaustion markers (CTLA-4, PD-1, TIM-3, LAG-3). Understanding this mechanism could clarify the role of DNA damage repair in immune dysfunction. The motivation behind this research stems from observing CD8+ T cell dysfunction in fibrosis and exploring how an impaired DNA damage response contributes to T cell exhaustion, potentially uncovering new insights into chronic diseases. 

The methodology involves: 

So far, key findings include increased exhaustion markers in shXRCC2 CD8+ T cells and a metabolic shift towards glycolytic respiration. A bulk RNA sequencing study is ongoing, with transcriptomics expected to conclude by late April. This research contributes to the broader field by advancing the understanding of DNA repair in immune dysfunction, particularly in lung fibrosis. It may reveal new mechanisms of immune failure in chronic diseases and introduce XRCC2-based therapies using extracellular vesicles as a potential treatment strategy for fibrosis. In real-world applications, this study could lead to cell-specific DNA repair-based therapies that reprogram immune cells to clear senescent cells, improve tissue regeneration, and reduce fibrosis. Additionally, insights from this work may open new therapeutic avenues for cancer and autoimmune diseases. While Aim 2 requires more time to complete, the long-term goal is to develop effective therapeutic strategies that target immune exhaustion and fibrosis.