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Recent Submissions

Therapeutic Role of Follistatin in Hypertension
(2026) Kuganathan, Ann; Krepinsky, Joan
Hypertension is a leading cause of morbidity and mortality worldwide. 1 in 5 Canadians have hypertension and a third of this population have uncontrolled high blood pressure (BP) even while on commonly prescribed antihypertensive treatments. Majority of hypertensive patients have high BP that develops from an unknown cause termed primary or essential hypertension. This is characterized by remodeling of small arteries called resistance vessels which is driven in part by oxidative stress. Most vessels are surrounded by perivascular adipose tissue (PVAT) which regulates vascular tone via release of vasoactive substances. In physiological conditions, PVAT releases more relaxing factors, promoting vasodilation. This anticontractile effect is reduced in hypertension due to elevated oxidative stress. Follistatin, an endogenous inhibitor of activins, reduces oxidative stress and induces adipose tissue browning – the conversion of white to brown adipose tissue – which is a process linked to improved vasorelaxation and lower blood pressure. Whether follistatin affects PVAT is unknown. We hypothesize that follistatin, through the amelioration of PVAT structure and function, improves vascular function and BP in a model of essential hypertension. In our first study, we demonstrated that follistatin lowered blood pressure in models of essential and secondary hypertension. Follistatin improved resistance vessel structure evidenced by reduced reactive oxygen species (ROS) and fibrosis. Vascular contraction was decreased and relaxation was improved by follistatin at least in part by the inhibition of ROS and activin A. Our second study investigated the effects of follistatin on the regulation of vascular function by PVAT. We discovered that follistatin treatment reduced ROS and increased markers of brown adipose tissue in PVAT around resistance vessels. Additionally, follistatin increased bioavailability and production of nitric oxide, a vasodilator, in PVAT through ROS inhibition. We describe mechanisms underlying these processes including the neutralization of activins and phosphorylation of AMPK in PVAT which restored its anticontractile effect. BP reduction alone using hydralazine, does not replicate beneficial effects on PVAT-mediated vascular function suggesting that follistatin directly affects PVAT to induce these effects. Our studies collectively demonstrate that follistatin effectively lowers BP and improves vascular function in both essential and secondary hypertension. Follistatin ameliorates vascular function through direct effects on PVAT highlighting the therapeutic potential of targeting PVAT and vascular function in the management of hypertension.
ELUCIDATING THE ROLE OF MICRORNA (MIR)-299A-5P IN ENHANCING FIBROSIS AND PRO-APOPTOTIC SIGNALLING PATHWAYS, THEREBY PROMOTING DIABETIC KIDNEY DISEASE.
(2026) Ifeanyi Kennedy Nmecha; Krepinsky, Joan; Medical Sciences
LAY ABSTRACT: Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, developing in up to 40% of patients with diabetes. DKD is the leading cause of kidney diseases globally, associated with reduced quality of life and increased mortality. A key early problem is the buildup of extracellular matrix proteins, mainly due to mesangial cell activation and proximal tubular cell damage. The major goal of my research is to show the role that microRNA-299a-5p plays in promoting kidney damage over time in DKD. My research showed that in a diabetic setting microRNA-299a-5p is increased, and this in turn reduces the antifibrotic proteins follistatin and cripto-1 thereby increasing the expression of the proteins known to promote kidney scarring, activin A and transforming growth factor β1 (TGFβ1). Since follistatin and cripto-1 naturally inhibit these fibrosis-promoting proteins, their suppression by microRNA-299a-5p worsens kidney damage. My research also showed that microRNA-299a-5p is elevated in diabetic kidneys from both mice and humans, as well as in mesangial cells exposed to high glucose. When we increased this microRNA, mesangial cells produced more extracellular matrix proteins, mimicking the effects of high glucose. Blocking microRNA-299a-5p, however, prevented these harmful effects. In a diabetic mouse model, inhibiting microRNA-299a-5p reduced kidney damage, preventing protein loss in urine (albuminuria), kidney enlargement, loss of important kidney cells (podocytes), and excessive extracellular matrix buildup. This was linked to higher levels of follistatin and cripto-1, suggesting that microRNA-299a-5p plays a key role in kidney fibrosis and may be a promising target for new treatments in DKD. Additionally, I showed that in the kidney proximal tubules, this microRNA causes damage and death to the tubules, a hallmark of DKD progression. The effect of the microRNA on the kidney proximal tubules is seen through the reduction of the anti-apoptotic mitogen activated protein 3 kinase 2 expression which eventually leads to the disruption of its signalling pathway. The studies in this thesis collectively emphasize the importance of microRNA-299a-5p inhibition in preventing the debilitating effects of DKD. Additionally, it provides a non-invasive method of detecting kidney disease progression by assessing the level of microRNA-299a-5p. As specific microRNAs are dysregulated early in the course of DKD even before significant kidney damage occurs, this makes them serve as both early biomarkers and therapeutic targets. Current treatments for DKD such as blood pressure control, glucose-lowering drugs, and medications that block the renin-angiotensin system can slow disease progression but often do not fully prevent kidney damage. These therapies mainly target symptoms or single pathways and are not tailored to the molecular drivers of the disease. However, microRNAs act as master regulators of gene expression and can control entire networks of genes involved in key disease processes such as inflammation, fibrosis (scarring), oxidative stress, and cell death. This means that targeting a single microRNA such as microRNA-299a-5p has the potential to modify multiple disease mechanisms at once, offering a broader and more upstream therapeutic approach. Lastly, this thesis provides a broader view of the targets of this microRNA, which if synthetically increased in DKD patients, has the potential of conferring protection against kidney decline. By correcting microRNA imbalances, we could intervene earlier and more precisely, moving from a “one-size-fits-all” model towards personalized, mechanism-based treatment that addresses the root causes of DKD rather than just its consequences. SCIENTIFIC ABSTRACT: Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, affecting up to 40 percent of individuals with the condition. As the leading cause of end stage kidney disease, DKD significantly diminishes quality of life and contributes to increased mortality. In Canada, approximately one in ten people, equivalent to four million individuals, are affected by some form of kidney disease. This imposes an estimated annual cost of forty billion dollars on the healthcare system for treatment and management of the disease. A hallmark of early DKD progression is the accumulation of extracellular matrix proteins within the glomerulus, primarily driven by mesangial cell activation. Despite extensive efforts to target the underlying molecular mechanisms of DKD, the search for optimal biomarkers and effective therapeutic targets remains ongoing. There is a critical need to identify novel molecular targets and therapeutic strategies to improve clinical outcomes for patients with this debilitating condition. Recent studies have highlighted microRNAs (miRs) as promising candidates for both diagnostic and therapeutic applications. Given that miR expression profiles are often altered in disease states such as DKD, they offer a compelling avenue for the development of innovative interventions. The first study in this thesis investigates the role of the novel miR-299a-5p in promoting fibrosis and the accumulation of extracellular matrix proteins in the kidneys of type 1 diabetic Akita mice. This miR was found to be significantly upregulated in human diabetic kidney biopsies and in kidneys across multiple mouse models of type 1 diabetes. Bioinformatic analyses identified cripto-1 and follistatin as direct targets of miR-299a-5p through binding to their respective 3' untranslated regions. Follistatin is a well-established anti-fibrotic protein that inhibits activin A, while cripto-1 suppresses transforming growth factor beta 1 (TGFβ1), both of which are key pro-fibrotic cytokines. In vitro studies using primary mesangial cells showed that miR-299a-5p was expressed in these cell lines and validated our previous findings, which demonstrated that overexpression of miR-299a-5p significantly reduced the basal expression of cripto-1 and follistatin while enhancing the expression of fibrotic proteins. Conversely, inhibition of miR-299a-5p prevented high glucose-induced fibrotic protein expression and restored basal levels of cripto-1 and follistatin. Interestingly, co-administration of cripto-1 and follistatin produced an additive anti-fibrotic effect in the presence of miR-299a-5p overexpression. Building upon these findings, the therapeutic relevance of miR-299a-5p inhibition was assessed in vivo using type 1 diabetic Akita mice overexpressing TGFβ1, a model characterized by kidney fibrosis. Inhibition of miR-299a-5p using locked nucleic acid technology led to significant reductions in albuminuria, kidney hypertrophy, and fibrosis. Notably, circulating miR-299a-5p which we suspect were packaged as extracellular vesicles (exosomes) was detected in the serum of these diabetic mice, supporting its potential utility as a non-invasive biomarker in diabetic kidney disease. The second study focuses on the role of miR-299a-5p in proximal tubular apoptosis, an increasingly recognized contributor to DKD progression beyond glomerular injury. We identified mitogen-activated protein kinase kinase kinase 2 (MAP3K2), which is highly expressed in proximal tubules, as a direct target of miR-299a-5p. MAP3K2 activates extracellular signal-regulated kinase 5 (Erk5), a kinase involved in anti-inflammatory and anti-apoptotic pathways via activation of zinc finger transcription factors such as the Kruppel-like factor family and nuclear factor erythroid 2-related factor 2. Using human proximal tubular cells which expressed this miR, we showed that inhibition of miR-299a-5p attenuated high glucose-induced tubular apoptosis and preserved the protein expression of both MAP3K2 and Erk5. Recognizing the importance of sex as a biological variable in disease pathogenesis, the final study of this thesis describes the development of a robust mouse model to study sex differences in DKD progression. A high dose treatment with streptozotocin protocol was optimized to induce comparable type 1 diabetes in both male and female CD1 mice. Using this model, we demonstrate that DKD develops similarly in both sexes, thereby enabling future studies to assess sex-specific expression patterns of miR-299a-5p and to determine whether its regulation is modulated by diabetic pathology.
Examining and Addressing Methodological Gaps To Enhance the Trustworthiness and Relevance of Systematic Reviews and Clinical Practice Guidelines
(2026) Oliveros Sepúlveda, María José; Brignardello-Petersen, Romina; Santesso, Nancy; Guyatt, Gordon; Clinical Health Sciences (Health Research Methodology)
Systematic reviews (SRs) and clinical practice guidelines play a central role in healthcare decision making by synthesising and interpreting evidence to provide actionable recommendations. Their usefulness depends not only on methodological rigor, but also on whether the evidence they summarise reflects outcomes that matter to patients. When methodological decisions prioritise convenience over relevance, or when patient-important outcomes (PIOs) are inconsistently measured or poorly characterised, the resulting evidence may fail to support patient-centred decisions and contribute to avoidable research waste. This thesis applies a methodological lens to key stages of the evidence-to-decision pathway to examine how methodological choices shape the trustworthiness, relevance, and patient-centredness of health evidence. It focuses on decisions made during evidence synthesis and guideline development. Specifically, it evaluates how including conference abstracts can influence SR conclusions, how SRs report and synthesise outcomes that matter to patients, and how patient-reported outcomes (PROs) can be better integrated into the process of moving from evidence to recommendations. Using both empirical and conceptual approaches, this work offers three methodological contributions. First, it shows that the impact of including conference abstracts is context dependent and constrained by reporting limitations. Second, it shown that PIOs are underrepresented in SRs of rehabilitation. Third, it provides guidance to improve the integration of PROs into guideline development. Collectively, these findings identify practical opportunities to strengthen methodological rigor and enhance patient-centred healthcare decisions.
Digital Research Commons Pilot - Strategic Plan Summary
(2024-11) Brodeur, Jay; Di Nello, Angela; Scott, Rigel
The Digital Research Commons Pilot (DRCP) was a three-year project to build a more connected, capable, and researcher-focused digital research infrastructure (DRI) ecosystem at McMaster. Read about the DRCP's vision, mission, goals and objectives.
GENERATING AN ADAPTER BASED UNIVERSAL T CELL THERAPY FOR CANCER
(2026) Serniuck, Nickolas J; Rullo, Anthony; Bramson, Jonathan; Chemical Biology
T cells present a powerful tool for cancer treatment given their ability to circulate throughout the body and “seek out and destroy” tumor deposits. The infusion of cancer patients with tumor-specific T cells is now a clinically proven treatment for cancer with six currently available. Accessibility to this promising therapeutic is limited by the requirement for the per-patient and per-target manufacturing of therapeutic T cells. Conventional synthetic antigen receptors (SARs) are rigid and typically limited to one tumor target. Given the vast number of potential targets this introduces significant timing, logistic and cost challenges when applying this approach broadly. Our program seeks to overcome these challenges by creating an on demand “off-the-shelf” solution. We propose the use of Universal SARs that can be programmed with target specificity after the engineered T cells are manufactured. A universal SAR employs an acceptor moiety which binds a molecular adapter that links the T cell to the tumor. By creating a library of adapters, a T cell engineered with a single universal SAR can be directed against multiple tumor targets. We have developed molecular adapters, termed covalent immune recruiters (CIRs), that chemically link immune receptors to cancer cells. Our grand vision is an offthe- shelf engineered T cell that is purpose-built for on demand CIR-mediated targeting and a library of CIRs directed against an array of tumor targets to yield a dynamic and affordable personalized therapy.

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