Publications by authors named "Kelly Tam"

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We developed a novel "two-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF.

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Background: Heart failure with preserved ejection fraction (HFpEF) currently accounts for more than half of patients with HF, with limited approved evidence-based therapies. HFpEF is a complex multifactorial disease associated with hypertension, obesity, diabetes, and renal dysfunction. In addition to our limited understanding of HFpEF pathophysiology, the development of new therapies is partially hindered by the existing translationally relevant preclinical HFpEF models.

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The lymphatic vascular system spans nearly every organ in the body and serves as an important network that maintains fluid, metabolite, and immune cell homeostasis. Recently, there has been a growing interest in the role of lymphatic biology in chronic disorders outside the realm of lymphatic abnormalities, lymphedema, or oncology, such as cardiovascular-kidney-metabolic syndrome (CKM). We propose that enhancing lymphatic function pharmacologically may be a novel and effective way to improve quality of life in patients with CKM syndrome by engaging multiple pathologies at once throughout the body.

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Unlabelled: Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel "2-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF.

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The Rpd3L histone deacetylase (HDAC) complex is an ancient 12-subunit complex conserved in a broad range of eukaryotes that performs localized deacetylation at or near sites of recruitment by DNA-bound factors. Here we describe the cryo-EM structure of this prototypical HDAC complex that is characterized by as many as seven subunits performing scaffolding roles for the tight integration of the only catalytic subunit, Rpd3. The principal scaffolding protein, Sin3, along with Rpd3 and the histone chaperone, Ume1, are present in two copies, with each copy organized into separate lobes of an asymmetric dimeric molecular assembly.

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Article Synopsis
  • cGMP-dependent protein kinase 1α (PKG1α) supports heart function in response to pressure overload, but its activation often leads to hypotension, which limits its therapeutic use in heart failure.* -
  • The study found that mixed lineage kinase 3 (MLK3) interacts with PKG1α and is crucial for maintaining left ventricle (LV) function without affecting blood pressure (BP), even in conditions of heart failure.* -
  • Results indicate that enhancing MLK3 activity could help improve heart function in heart failure patients while preventing the drop in blood pressure typically associated with PKG1α activation.*
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Background: Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies.

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Article Synopsis
  • Sacubitril/valsartan (Sac/Val) is a treatment for heart failure that works by preventing the breakdown of natriuretic peptides, potentially enhancing cGMP-PKG signaling.
  • Researchers studied the impact of Sac/Val on mice with a specific mutation affecting PKG to see if it was necessary for the drug's effectiveness.
  • Despite the mutation, Sac/Val still improved heart structure and function in mice, indicating that other signaling pathways aside from the natriuretic peptide-cGMP-PKG pathway may also contribute to its benefits in heart failure.
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  • Transverse aortic constriction (TAC) is a mouse model used to study heart issues caused by increased pressure, and the severity of the constriction is determined by the size of the needle used during surgery.* -
  • In a study, adult male mice underwent TAC surgery with different needle gauges (25G, 26G, 27G) to assess how varying levels of constriction affected heart health over four weeks compared to control mice.* -
  • Results showed that tighter constriction (27G) led to more serious heart problems, including heart failure symptoms and kidney atrophy, while different constriction levels resulted in distinct cardiac responses, suggesting they could be useful in various research scenarios.*
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Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH-terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study, we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF.

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Mentholated cigarettes capture a quarter of the US market, and are disproportionately smoked by adolescents. Menthol allosterically modulates nicotinic acetylcholine receptor function, but its effects on the brain and nicotine addiction are unclear. To determine if menthol is psychoactive, we assessed locomotor sensitization and brain functional connectivity.

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Introduction: Individuals with attention deficit/hyperactivity disorder (ADHD) are susceptible to earlier and more severe nicotine addiction. To shed light on the relationship between nicotine and ADHD, we examined nicotine's effects on functional brain networks in an animal model of ADHD.

Methods: Awake magnetic resonance imaging was used to compare functional connectivity in adolescent (post-natal day 44 ± 2) males of the spontaneously hypertensive rat (SHR) strain and two control strains, Wistar-Kyoto and Sprague-Dawley (n = 16 each).

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Introduction: It is unknown how the timing between doses might affect nicotine's impact on neural activity. Our objective was to examine how the interdose interval affects nicotine's impact on resting-state functional connectivity (rsFC).

Materials And Methods: Adult male Sprague-Dawley rats were administered nicotine daily (0.

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Traumatic brain injury (TBI) is characterized by neuronal damage and commonly, secondary cell death, leading to functional and neurological dysfunction. Despite the recent focus of TBI research on developing therapies, affective therapeutic strategies targeting neuronal death associated with TBI remain underexplored. This study explored the efficacy of granulocyte-colony stimulating factor (G-CSF) as an intervention for improving cognitive deficits commonly associated with TBI.

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