2025 Fellowship Winners

Project short description: Cutaneous melanoma is the most aggressive and deadly form of skin cancer, one of the fastest growing types of cancers worldwide. Mutations in NRAS account for roughly 20% of melanoma cases, and NRAS-mutant melanomas lack specific and effective treatments as well as being beset by treatment resistance. In addition, treatment options become limited in the instance of resistance and subsequent progression. As such, new avenues of treatment strategies are needed in order to improve patient outcomes. One such area that will be investigated in this project is that of targeting mitochondria and its quality control mechanism, mitochondrial dynamics. Despite emerging evidence suggesting that mitochondrial dynamics regulate progression and resistance mechanisms in other cancers through mediating alterations in metabolism and cell fate signalling, their role in NRAS-mutant melanoma remains unexplored. Preliminary data suggested that elevated expression of core mitochondrial fission regulators Drp1 and MIEF2 was associated with poorer survival, pro-oncogenic signalling cascades, and immune evasion in NRAS melanoma patients. By quantifying the expression of Drp1 and MIEF2 in NRAS melanoma patient tissue, as well as investigating both tumour cell behaviour as well as mitochondrial morphology and metabolism in NRAS cell lines following CRISPR/Cas9 knock-out of Drp1 or MIEF2, this project will determine whether targeting mitochondrial dynamics represents a functional vulnerability and a preclinical rationale for a novel treatment strategy for this clinically significant cancer subtype. 

Fertilization, the union of sperm and egg, is the fundamental biological event that initiates the development of all sexually reproducing organisms. Despite its importance, the molecular mechanisms underlying sperm-egg fusion remain poorly understood. My postdoctoral work has contributed to elucidating these mechanisms by our breakthrough discovery of a conserved sperm complex that mediates sperm-egg interaction across vertebrates (Deneke, Blaha et al., 2024). Our recent unpublished findings show that this complex is composed of even more factors which are conserved in humans, linking all previously known factors into one multi-subunit complex, the SPARK complex. However, how the SPARK complex mechanistically drives membrane fusion remains unclear, and uncovering this fundamental gap in knowledge will be required to understand how fertilization works. I propose a two-step model driving vertebrate fertilization: the SPARK complex is first activated by egg receptor binding and subsequently triggered for fusion by membrane proximity. To test this model, I will first determine how egg receptors in fish and mammals modulate the SPARK complex to initiate fusion competency (Aim 1). Second, I will map functionally critical "hotspots" and fusogenic domains within the complex to identify the conformational changes required for membrane insertion and fusion (Aim 2). I will employ zebrafish as the primary model system as their external fertilization, abundant gamete supply, and molecular conservation with humans make them ideally suited for biochemical and structure-function studies. My findings will elucidate the molecular mechanisms of sperm-egg fusion and have direct implications for understanding idiopathic infertility, improving assisted reproductive technologies (ART), and developing novel contraceptive strategies. 

Chronic psychosocial stress is a strong predictor of morbidity and premature mortality and is associated with immune changes that closely resemble aging, including myeloid bias, chronic inflammation, and stem cell expansion (1-5). Yet how a transient psychosocial experience produces a durable, aging-like biological imprint remains unresolved. Our preliminary data from chronic social defeat stress indicate that hematopoietic stem cells (HSCs) activate an innate antiviral-like sensing program accompanied by metabolic rewiring and altered chemokine tone. We propose that these stress-evoked signals write persistent chromatin programs in HSCs that phenocopy immune aging, leading to sustained inflammatory output and reduced regenerative capacity of blood stem and progenitor cells. We hypothesize that psychosocial stress engages innate sensing pathways in HSCs to install long-lived epigenetic programs that bias hematopoiesis toward inflammatory aging at the expense of immune regeneration. We will: (i) define stress-induced immune aging trajectories by integrating longitudinal immunophenotyping with single-cell epigenomic profiling across tissues; (ii) link persistent epigenomic imprints in HSCs to functional decline in immune responsiveness and clonal output; and (iii) establish causality and reversibility by transiently blocking key “writer” pathways during the imprinting window and assessing long-term rescue of chromatin state, clonal architecture, and immune function. Together, our work will identify stress-induced HSC reprogramming as a modifiable driver of premature immune aging, reveal critical intervention windows, and uncover actionable targets to preserve immune regeneration and promote a healthy lifespan. 

Aging is an irreversible physio-pathological process leading to the progressive decline of biological functions critical for survival. Although some age-related changes can be considered benign features, bad aging is associated with the loss of homeostatic defense and progressive deterioration of biological functions. Indeed, aging is a risk factor for chronic diseases, increasing interest in basic and clinical research. It is known that inflammation and oxidative stress represent key factors contributing to aging-induced alterations in tissue function. Of note, Interleukin-6 (IL-6) is considered a potential connecting link between inflammation and oxidative stress. Moreover, IL-6 serum levels were strongly associated with mortality in very old people, however, how high IL-6 levels contribute to age-related alterations still remains a missing link in biomedical research. To this end, the main goal of this project is to define the action of IL-6 during aging and to identify protective mechanisms induced by inhibition of IL-6 transignalling on age-associated defects. Here we propose a pharmacological approach specifically targeting with the soluble IL-6 receptor (sIL-6R), which promotes pro-inflammatory and catabolic effects induced by IL-6. An important mechanism associated with cell aging is DNA methylation, an index of “good and bad” aging. DNA methylation analysis of specific clocks will determine whether the inhibition of a key factor, such as sIL-6R, contributing to oxy-inflammation can induce biological rejuvenation. Thus, the proposed project will focus on three specific aims: i) To monitor the aging process in IL-6 transignalling blockade mice; ii) To assess skeletal muscle integrity in aged mice under IL-6 transignalling blockade; iii) To evaluate if IL-6 transignalling blockade rejuvenates tissues via epigenetic clock modulation. 

Sjögren’s disease (SjD) is a systemic autoimmune disorder characterized by chronic inflammation of the salivary glands, leading to sicca symptoms, fatigue, pain, and a markedly increased risk of B-cell lymphoma. Despite its high disease burden, therapeutic options remain limited to symptomatic management, reflecting an incomplete understanding of the cellular and molecular mechanisms sustaining chronic glandular inflammation. While immune dysregulation is a hallmark of SjD, emerging evidence suggests that stromal cells actively shape inflammatory niches within the affected tissue. However, the nature and functional relevance of immunestromal interactions in SjD remain poorly defined. This project aims to dissect the immune-stromal crosstalk that drives persistent inflammation and glandular dysfunction in SjD by combining single-nuclear (sn) multiome profiling with functional validation. Using matched minor salivary gland (MSG) biopsies and peripheral blood samples from well-characterized SjD patients, the project will generate an integrated transcriptomic and epigenomic tissue and peripheral blood atlas. This approach will enable the identification of disease-specific cellular populations, regulatory programs, and intercellular communication networks that sustain chronic inflammation. Key immune-stromal interaction pathways emerging from these analyses will be functionally tested using ex vivo co-culture systems and precision-cut salivary gland tissue slices to establish causality and therapeutic relevance. Overall, this project seeks to provide a mechanistic framework for how immune and stromal cells cooperate to perpetuate SjD pathology. By uncovering novel regulatory circuits and interaction networks, it aims to identify candidate pathways for targeted intervention, ultimately contributing to the development of disease-modifying strategies for SjD.

Liver regeneration after partial hepatectomy requires the coordinated restoration of hepatocyte polarity, sinusoidal organization and bile canalicular networks. Although the molecular pathways of regeneration are well characterized, the three-dimensional structural principles that guide effective tissue repair are still poorly understood. Highresolution imaging reveals that organs encode repair progress through quantifiable spatial patterns, yet no framework currently exists to learn these patterns across the regenerative process. This project will develop an artificial intelligence based approach to identify the latent geometric signatures that characterize successful liver regeneration. Using single-cell resolved 3D confocal datasets from early regenerative stages, we will extract multi-scale descriptors of polarity orientation, local alignment fields, epithelial organization, sinusoidal topology and bile canaliculi connectivity. These descriptors will be integrated through graph-based representation learning and manifold modeling to build a Regeneration Map: a low-dimensional representation that traces the progression of architectural states during repair. From this learned representation, we will compute a 'Regeneration Score' that provides an interpretable measure of regenerative progression based solely on tissue architecture. The score has the potential to detect early deviations associated with impaired repair, aging or metabolic dysfunction, offering a new structural perspective for evaluating tissue health. The project will be carried out at Universidad de Las Américas-Quito using an established reconstruction pipeline and accessible computational tools. All methods will be released as open-source resources with minimal hardware requirements, supporting adoption in laboratories with limited infrastructure. By combining regenerative biology, quantitative morphology and AI, the project creates a new framework for understanding liver regeneration.