Michele Sainvil, MD
Project Title: A Prospective Patient-centered Exploration of Barriers and Facilitators to Stool Biospecimen Banking among Minoritized Patients Undergoing Hematopoietic Cell Transplantation (HCT)
Mentor: Anthony Sung, MD; Tamara Somers, PhD
Training Track: Cellular Therapy, Track III
Award Years: 2023-2025
Project Description: Cellular therapies like Hematopoietic Stem Cell Transplantation (HCT) and Chimeric-Antigen Receptor T-cell therapy (CAR-T) are curative for high-risk hematologic malignancies. However, medically underserved patient populations encounter barriers to care, leading to disparities closely linked to social determinants of health. These disparities, including limited access to education, socioeconomic status, and healthcare access, contribute to reduced enrollment in clinical trials and unequal access to life-saving therapies. Notably, health disparities in biobanking enrollment among HCT patients further hinder research representation, impeding advancements in personalized medicine, and leading to poorer outcomes despite comparable HCT acceptance rates. Studies have emphasized the underrepresentation of minoritized participants in biobanks, limiting research diversity. We propose collecting longitudinal stool specimens in a biospecimen repository, from HCT patients at Duke University Cancer Center, generating large-scale data for a comprehensive understanding of microbiome variations. However, to date, the participation of minoritized patients remains lag.
We propose a prospective mixed methods study to identify factors leading to poor stool biospecimen study enrollment in minoritized participants during stem cell transplantation. Understanding the factors influencing poor stool biospecimen enrollment and collection in minoritized participants. By developing a culturally sensitive question guide and conducting interviews, we seek to explore consent rates, variations in participation, and potential interventions to enhance inclusivity in research. Uncovering specific challenges fosters a deeper understanding of barriers to biospecimen and clinical trial research participation, informing targeted interventions to bridge disparities, increase participation, and improve access to personalized medicine for historically minoritized populations undergoing HCT.
Katherine Zhou, MD, PhD
Project Title: Canonical and non-canonical functions of the snoRNA Snord67 in the regulation of alternative splicing and modulation of the immune system
Mentor: Chad Pecot, MD; Christopher Holley, MD, PhD
Training Track: IV, MOLECULAR BIOLOGY, SIGNALING & GENETICS
Award Years: 2023-2025
Project Description: Small nucleolar RNAs (snoRNAs) are small noncoding RNAs that guide post-transcriptional 2′-O-methylation and pseudouridylation of ribosomal RNAs and small nuclear RNAs. In addition to these canonical roles, snoRNAs have non-canonical functions including the modification of messenger RNAs and microRNAs, as well as the regulation of transcription and post-transcriptional processing. Recent work in the Pecot lab has demonstrated that the snoRNA Snord67 promotes aberrant cell proliferation and migration in lymph nodes. Knockout of Snord67 led to widespread changes in alternative splicing, as well as decreased cell proliferation. However, the mechanisms underlying these phenotypes remain unclear. The goal of my research project is to investigate the canonical and non-canonical mechanisms by which Snord67 leads to changes in alternative splicing and changes in cellular phenotype.
Project Title: Butylparabens Molecular and Clinical Effects on Sickle Cells Patients
Mentor: Huanghe Yang, PhD
Training Track: IV, Molecular Biology, Signaling & Genetics
Award Years: 2024-2026
Project Description:
SCD is a major public health concern, affecting an estimated 100,000 Americans and 7.74 million individuals worldwide. Characterized by vaso-occlusive crisis (VOC), anemia, and thrombosis, SCD’s manifestations lead to significant morbidity and mortality. Despite advancements in understanding its molecular pathology and the development of sophisticated therapeutics, the availability of cost-effective treatments to prevent these life-threatening manifestations remains inadequate. This highlights the urgent need for a deeper understanding of the underlying pathophysiological mechanisms of SCD to develop targeted, precision therapeutics that can effectively mitigate complications associated with sickling.
There are emerging concerns about the safety of parabens especially butylparaben (BuP), a widely used preservative in personal care products, cosmetics, foods and pharmaceuticals such as acetaminophen, ibuprofen and opioids. The overarching goal of this study is to evaluate the unknown risk of BuP in triggering sickle cell disease (SCD) manifestations and dissect the underlying molecular mechanism. Understanding the molecular basis of BuP’s adverse effect on sickle red blood cells (RBCs) not only imposes a warning to SCD patients who exposed BuP, but also offers a promising avenue for developing novel therapeutic strategies to counteract the deleterious impacts of this common preservative.
Project Title: Dual Modulation of Allosteric and Vasoregulatory Function in Sickle Red Blood Cells
Mentor: Timothy McMahon, MD, PhD
Training Track: Training Track: I, Transfusion Medicine and Hemoglobinopathies
Award Years: 2024-2026
Project Description: Sickle cell disease (SCD) represents a significant global health burden, characterized by hemolytic anemia, vaso-occlusive crises, and end-organ damage. While gene therapy holds promise, recent therapeutic approaches targeting RBC-specific pyruvate kinase (PKR) activation, such as etavopivat (FT-4202) and mitapivat (AG-348), offer novel avenues for intervention. PKR activation in SCD RBCs decreases effector 2,3-diphosphoglycerate (DPG or BPG) and increases intracellular ATP levels; both of these changes may be beneficial. ATP is essential for maintenance of RBC hydration and membrane integrity. ATP exported by the RBCs in presence of PKR activator (PKRA) has not yet been investigated in detail. We have preliminary data which reports increase in supernatant (exported) ATP in healthy red cells treated with AG-348 under conditions of hypoxia. We aim to determine if the ATP-related benefit of PKR activators occurs from only intrinsic increase in ATP or both the intrinsic and the extrinsic rise in ATP. Extrinsic ATP may contribute to antiadhesive activity, vasodilation, and favorable modulation of vascular permeability; these have not been investigated in detail.
Beyond PKR activators, there are other emerging multimodal (allosteric and vasoregulatory) therapies relevant to SCD. One such novel agent is VZHE039-NO. It is a dual-action aromatic aldehyde that functions as a positive allosteric effector and incorporates a NO-donating adduct. VZHE additionally has a secondary anti-sickling action through their ability to destabilize HbS polymer formation. Our proposed research intends to elucidate the dual modulation of function in SCD RBCs through allosteric and vasoregulatory actions of novel approaches, shedding light on their clinical implications.
