Heart failure is a leading cause of morbidity and mortality worldwide. The search for effective treatments hinges upon understanding the molecular underpinnings of the adverse hypertrophy and remodeling that precipitates cardiac failure. Recent research implicates endoplasmic reticulum (ER) stress as a virtually universal feature of heart diseases, but detailed mechanisms of how ER stress contributes to maladaptive cardiac remodeling are currently lacking. My colleagues and I recently developed a novel technological platform and used it to discover that cardiac remodeling amid ER stress is associated with widespread disruption in protein turnover dynamics, including importantly a cluster of ER-associated glycoproteins with aberrant proteostasis. Within the cluster, cardiac remodeling in particular severely disrupts the dynamics and glycosylation of neuropilin-1 (NRP1), a cell surface glycoprotein that is thought to be salubrious to the failing heart. These observations endorse my postulate that ER stress contributes to maladaptive remodeling via effecting aberrant cardiac protein homeostasis and glycosylation. Hence, the goal of the current proposal is to define the molecular consequences of ER stress in the myocardium by investigating three proteostasis parameters - protein expression, turnover dynamic and glycosylation - amid ER stress and cardiac remodeling. The short-term (K99) aims are to (1) understand how ER stress impacts the expression and dynamics of ER-associated proteins in mouse models, and (2) characterize the impact of protein dynamics and glycosylation on cardiac NRP1 protein interactions in health and in disease. These studies are a logical extension of my current research, and will give me opportunities to train in rodent and cell culture models of ER stress and cardiac remodeling, as well as translational studies of clinical human heart failure samples. With this development in mind, my long-term (R00) aims are to (3) investigate how protein glycosylation remodels in the cardiac proteome at large, using a combination of in vitro and in vivo models I will have trained in during my K99 phase, and (4) investigate how protein glycosylation impacts the physiological role of NRP1 signaling in the failing heart. The propose studies will be the first to systemically examine how ER stress impacts the essential ER functions of protein turnover and glycosylation as a pathogenic mechanism, and will thereby lend insights to our understanding of adverse remodeling. Altogether, the training plan and supportive institutional environment at UCLA will equip me with the experimental and career skills to ask a wide range of questions regarding ER stress and hypertrophy as an independent tenured faculty.
Heart failure is a leading cause of death for which effective treatments are severely lacking, whereas endoplasmic reticulum (ER) stress is a hallmark of the failing heart and contributes fundamentally to pathogenic processes. We identified that ER stress in early heart failure is associated with perturbed homeostasis of ER proteins and glycoproteins, which could negatively impact many cell surface receptor signaling pathways. Understanding how ER stress, protein turnover, and protein glycosylation mutually regulate one another would be relevant to identifying new drug targets for heart failure.
| Lau, Edward; Cao, Quan; Lam, Maggie P Y et al. (2018) Integrated omics dissection of proteome dynamics during cardiac remodeling. Nat Commun 9:120 |
| Lam, Maggie P Y; Ping, Peipei; Murphy, Elizabeth (2016) Proteomics Research in Cardiovascular Medicine and Biomarker Discovery. J Am Coll Cardiol 68:2819-2830 |
| Lam, Maggie P Y; Lau, Edward; Ng, Dominic C M et al. (2016) Cardiovascular proteomics in the era of big data: experimental and computational advances. Clin Proteomics 13:23 |
| Lam, Maggie P Y; Venkatraman, Vidya; Xing, Yi et al. (2016) Data-Driven Approach To Determine Popular Proteins for Targeted Proteomics Translation of Six Organ Systems. J Proteome Res 15:4126-4134 |
| Lam, Maggie P Y; Vivanco, Fernando; Scholten, Arjen et al. (2012) HUPO 2011: The new Cardiovascular Initiative - integrating proteomics and cardiovascular biology in health and disease. Proteomics 12:749-51 |
