Frank C Church

University of North Carolina at Chapel Hill | UNC · Department of Pathology and Laboratory Medicine

This commentary is about running an academic research laboratory group, including some reflections, memories, and tips on effectively managing such a group of scientists focused on one’s research. The author’s academic career has spanned from 1982 to 2022, including postdoctoral research associate through the rank of professor with tenure. Currentl...

The COVID-19 pandemic, caused by SARS-CoV-2, continues to impact global health regarding both morbidity and mortality. Although SARS-CoV-2 primarily causes acute respiratory distress syndrome (ARDS), the virus interacts with and influences other organs and tissues, including blood vessel endothelium, heart, gastrointestinal tract, and brain. We are...

The impacts of the COVID-19 pandemic throughout the world continue. These impacts influence many aspects of life, work, healthcare, and education in the U.S., which are drastically affected by the COVID-19 pandemic. Thus, a considerable challenge to tertiary-level education has been how to adapt our teaching styles and modalities to keep all stakeh...

Effective undergraduate courses increasingly blend elements of active learning with a more traditional lecture format. Designing and implementing active learning sessions that engage, educate, and are challenging and workable in a group setting are essential for student learners. In addition, active learning sessions take concepts of fundamental kn...

Introduction Medical students find immunology difficult to understand and relate to clinically and are often frustrated by the amount of detailed material. We created PRIME Immunology: Preview or Review of Important Material for Everyone: (i) video modules, (ii) Instagram site, and (iii) vocabulary files called Immunology Language. Methods The sel...

Advanced age is associated with an increased risk for falls in aging adults. Older adults are also more likely to be diagnosed with Parkinson’s disease (PD), with advanced age as the most significant risk factor. PD is a neurodegenerative disorder with four Cardinal motor symptoms: rigidity, bradykinesia, postural instability, and tremor. Thus, peo...

Parkinson’s disease (PD) usually presents in older adults and typically has both motor and non-motor dysfunctions. PD is a progressive neurodegenerative disorder resulting from dopaminergic neuronal cell loss in the mid-brain substantia nigra pars compacta region. Outlined here is an integrative medicine and health strategy that highlights five tre...

Parkinson's disease (PD) is a progressive neurodegenerative disorder brought about due to dopaminergic neuronal cell loss in the midbrain substantia nigra pars compacta region. PD presents most commonly in older adults and is a disorder of both motor and nonmotor dysfunction. The novel SARS-CoV-2 virus is responsible for the recent COVID-19 pandemi...

Active learning improves undergraduate STEM course comprehension; however, student comprehension using different active learning methods and student perception of active learning have not been fully explored. We analyze ten semesters (six years) of an undergraduate biology course (honors and non-honors sections) to understand student comprehension...

Parkinson disease (PD) is the second most common neurodegenerative disorder with approximately 60 000 newly diagnosed patients yearly in the United States. PD is traditionally described as a motor system condition, although numerous nonmotor symptoms exist, and typically manifest within elderly patients. The hallmark pathogenesis of PD is the loss...

While we are still learning more about COVID-19, caused by the novel SARS-CoV-2 virus, finding alternative and already available methods to reduce the risk and severity of the disease is paramount. One such option is vitamin D, in the form of vitamin D3 (cholecalciferol) supplementation, due to its potential antiviral properties. It has become appa...

Parkinson's disease (PD) is a progressive degenerative nervous system disorder and is the second most common neurodegenerative disorder in the elderly population. The disease originates from the loss of dopamine-producing neurons in the substantia nigra in the brain, resulting in unregulated activity of the basal ganglia. Αlpha-synuclein (α-syn) is...

The serine protease inhibitor (serpin) protein C inhibitor (PCI; also named plasminogen activator inhibitor-3) regulates serine proteases in hemostasis, fibrinolysis, and reproduction. The biochemical activity of PCI is not fully defined partly due to the lack of a convenient expression system for active rPCI. Using pET-15b plasmid, Ni2+-chelate an...

Plasminogen activator inhibitor-1 (PAI-1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI-1 should be beneficial in downregulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI-1 are associated with a poor prog...

Background: Angiotensin II (Ang II) plays an important role in cardiovascular disease. It also leads to the activation of coagulation. The coagulation protease thrombin induces cellular responses by activating protease-activated receptor 1 (PAR-1). We investigated whether PAR-1 contributes to Ang II-induced cardiovascular remodeling and inflammati...

Blood coagulation is a critical element of host defense. The ability of blood to clot when a vessel has been damaged, yet keep the clot localized to the site of injury, indicates the tenuous challenge that is required for maintenance of hemostasis. The balance between hemostasis, hemorrhage, and thrombosis is achieved by tight regulation of procoag...

The Side Effects of Drugs Annuals form a series of volumes in which the adverse effects of drugs and adverse reactions to them are surveyed. The series supplements the contents of Meyler's Side Effects of Drugs: the International Encyclopedia of Adverse Drug Reactions and Interactions. This review of the January 2012 to June 2013 publications on dr...

Purpose of review: The fibrinolytic system plays a key role in the regulation of hemostasis and thrombosis; however, it also has multiple pleiotropic effects. In this review, we examine the studies that investigated the role of the plasminogen activator system and its inhibitors outside the context of clot lysis. Recent findings: Activators of p...

Venous thromboembolism (VTE) encompasses both deep vein thrombosis (DVT) and pulmonary embolism (PE), a very serious and potentially lethal complication of DVT [1]. The strongest but most unchangeable risk factor for VTE is age [2]. After the age of 55, the risk of VTE goes up substantially and in those 75 years and older there is a ten-fold increa...

e14505 Background: The increased risk of thrombosis in patients with cancer has been well established. However, the triggers in these patients have yet to be fully defined. Under pathological conditions, the potent procoagulant protein Tissue Factor (TF) is found in the circulation and may trigger thrombosis. Methods: We evaluated the level of TF e...

Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In the present study, we analyzed tissue factor (TF) expression in 4 different human pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that 2 of the lines expressed TF and released TF-positive micropart...

Adipocytes express substances involved in both normal physiology and pathological processes. One such adipocyte protein is the Serpin (serine protease inhibitor) plasminogen activator inhibitor-1 (PAI-1). PAI-1 functions to inhibit urokinase type plasminogen activator (uPA) though PAI-1 itself is also implicated in breast cancer progression. While...

The conversion of prothrombin to thrombin is one of two non-duplicated enzymatic reactions during coagulation. Thrombin has long been considered an optimal anticoagulant target because it plays a crucial role in fibrin clot formation by catalyzing the cleavage of fibrinogen, upstream coagulation cofactors and platelet receptors. Although a number o...

Serpins (serine protease inhibitors) have traditionally been grouped together based on structural homology. They share common structural features of primary sequence, but not all serpins require binding to cofactors in order to achieve maximal protease inhibition. In order to obtain physiologically relevant rates of inhibition of target proteases,...

In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Uchida et al report the use of a urokinase plasminogen activator (uPA)−/− low-density lipoprotein receptor−/− mouse model to investigate the role of uPA in the development of abdominal aortic aneurysm (AAA) in a hyperlipidemic setting.1 Surprisingly, they show that uPA def...

Protease-activated receptor-1 (PAR-1) and PAR-2 are overexpressed in cancer cells and activation of these receptors contributes to malignancy. We have recently shown that thrombin activates PAR-1, which induces transactivation of PAR-2, resulting in increased plasminogen activator inhibitor-1 (PAI-1) expression in 4T1 murine mammary adenocarcinoma...

Heparin cofactor II (HCII) is a serine protease inhibitor (serpin) found in high concentrations in human plasma. Despite its discovery >30 years ago, its physiological function is still poorly understood. It is known to inhibit thrombin, the predominant coagulation protease, and HCII-thrombin complexes have been found in plasma, yet it is thought t...

Age-associated cellular senescence is thought to promote vascular dysfunction. p16(INK4a) is a cell cycle inhibitor that promotes senescence and is upregulated during normal aging. In this study, we examine the contribution of p16(INK4a) overexpression to venous thrombosis. Mice overexpressing p16(INK4a) were studied with 4 different vascular injur...

Epidemiologic studies have correlated elevated plasma fibrinogen (hyperfibrinogenemia) with risk of cardiovascular disease and arterial and venous thrombosis. However, it is unknown whether hyperfibrinogenemia is merely a biomarker of the proinflammatory disease state or is a causative mechanism in the etiology. We raised plasma fibrinogen levels i...

Activation of protease activated receptor-1 and −2 (PAR-1 and PAR-2) on tumor cells by coagulation proteases, such as factor Xa (FXa) and thrombin, leads to the expression of urokinase plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type-1 (PAI-1). uPA has been shown to contribute to malignancy by increasing tumor cell...

We investigated peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands effect on cell motility and the plasminogen activator system using normal MCF-10A and malignant MCF-10CA1 cell lines. Ciglitazone reduced both wound-induced migration and chemotaxis. However, the effect was not reversed with pretreatment of cells with the PPAR-γ-specific...

The coagulation and fibrinolytic systems contribute to malignancy by increasing angiogenesis, tumor growth, tumor invasion, and tumor metastasis. Oncogenic transformation increases the expression of tissue factor (TF) that results in local generation of coagulation proteases and activation of protease-activated receptor (PAR)-1 and PAR-2. We compar...

In hemostasis, the serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) functions to stabilize clots via inhibition of tissue plasminogen activator (tPA) with subsequent inhibition of fibrinolysis. In tissues, PAI-1 functions to inhibit extracellular matrix degradation via inhibition of urokinase plasminogen activator (uPA)....

Protein C inhibitor (PCI) is a plasma serine protease inhibitor (serpin) that regulates several serine proteases in coagulation including thrombin and activated protein C. However, the physiological role of PCI remains under investigation. The cysteine protease, cathepsin L, has a role in many physiological processes including cardiovascular diseas...

Activated protein C (APC), an anticoagulant serine protease, has been shown to have non-hemostatic functions related to inflammation, cell survival, and cell migration. In this study we investigate the mechanism by which APC promotes angiogenesis and breast cancer invasion using ex vivo and in vitro methods. When proteolytically active, APC promote...

Activation of tumor cell-associated coagulation and plasminogen activator pathways occurs in malignant disease processes, including breast cancer, and may promote metastatic activity. To compare the coagulation and plasminogen activator pathways of normal and metastatic cells, we examined two cell lines from the MCF-10 family of breast cells: near-...

Heparin cofactor II (HCII) is a serine protease inhibitor (serpin) that has been shown to be a predictor of decreased atherosclerosis in the elderly and protective against atherosclerosis in mice. HCII inhibits thrombin in vitro and HCII-thrombin complexes have been detected in human plasma. Moreover, the mechanism of protection against atheroscler...

Breast cancer is the most prominent cancer among females in the United States. There are a number of risk factors associated with development of breast cancer, including consumption of a high-fat diet and obesity. Plasminogen activator inhibitor-1 (PAI-1) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in b...

Here we tested the ability to augment the biological activity of the thrombin aptamer, d(GGTTGGTGTGGTTGG), by using locked nucleic acid (LNA) to influence its G-quadruplex structure. Compared to un-substituted control aptamer, LNA-containing aptamers displayed varying degrees of thrombin inhibition. Aptamers with LNA substituted in either positions...

Blood clotting proceeds through the sequential proteolytic activation of a series of serine proteases, culminating in thrombin cleaving fibrinogen into fibrin. The serine protease inhibitors (serpins) antithrombin (AT) and protein C inhibitor (PCI) both inhibit thrombin in a heparin-accelerated reaction. Heparin binds to the positively charged D-he...

Protein C inhibitor (PCI) is a plasma serine protease inhibitor (serpin) that inhibits several proteases in blood coagulation including thrombin, thrombin-thromobomodulin and activated protein C. Although PCI has been shown to inhibit these key blood coagulation proteases, a clearly defined hemostatic role for PCI remains to be elucidated. Prelimin...

Plasminogen activator inhibitor-1 (PAI-1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI-1 should be beneficial in downregulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI-1 are associated with a poor prog...

Background: Protein C inhibitor (PCI) and antithrombin (AT) are serine protease inhibitors (serpins) that inhibit a wide array of blood coagulation serine proteases including thrombin. Fifty-five Ala-scanned recombinant thrombin mutants were used to determine thrombin residues important for inhibition by PCI with and without the cofactors heparin a...

Hemostasis and fibrinolysis, the biological processes that maintain proper blood flow, are the consequence of a complex series of cascading enzymatic reactions. Serine proteases involved in these processes are regulated by feedback loops, local cofactor molecules, and serine protease inhibitors (serpins). The delicate balance between proteolytic an...

Activated protein C (APC) is a serine protease that regulates thrombin (IIa) production through inactivation of blood coagulation factors Va and VIIIa. APC also has non-hemostatic functions related to inflammation, proliferation, and apoptosis through various mechanisms. Using two breast cancer cell lines, MDA-MB-231 and MDA-MB-435, we investigated...

Increased levels of urokinase-type plasminogen activator (uPA) are associated with shortened overall survival in ovarian cancer patients. Additionally, elevated levels of the serine protease inhibitor (serpin), plasminogen activator inhibitor-1 (PAI-1), a uPA inhibitor, have also been correlated with an unfavorable prognosis in ovarian cancer. Ther...

See also Nishii Y, Cesar Gabazza E, Fujimoto H, Nakahara H, Takagi T, Bruno N, D'Alessandro-Gabazza CN, Maruyama J, Maruyama K, Hayashi T, Adachi Y, Suzuki K, Taguchi O. Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension. This issue, pp 2331–9.

Protein C inhibitor (PCI) is a plasma serine protease inhibitor (serpin) that regulates several serine proteases in coagulation and fibrinolysis including thrombin and activated protein C (APC). The physiological role of PCI, however, remains under investigation since PCI both inhibits and promotes thrombin generation. The cysteine protease, cathep...

Members of the serine protease inhibitor (serpin) superfamily play important roles in the inhibition of serine proteases involved in complex systems. This is evident in the regulation of coagulation serine proteases, especially the central enzyme in this system, thrombin. This review focuses on three serpins which are known to be key players in the...

Plasminogen activator inhibitor-1 (PAI-1) regulates the proteolytic activity of urokinase-type plasminogen activator (uPA) and there is increasing evidence for a PAI-1 role in regulating cell migration/invasion by other mechanisms like vitronectin (VN) binding and lipoprotein-receptor related protein (LRP) binding. We examined the role of PAI-1 to...

The serine protease inhibitor (serpin) protein C inhibitor (PCI) has been found in the prostate and possibly is a marker to distinguish normal prostate, benign prostatic hyperplasia, and prostate cancer. In this study, we assessed PCI expression in normal, hyperplastic, and malignant prostatic tissues, prostate cancer cell lines, and the CWR22 pros...

The serine protease inhibitor (serpin) protein C inhibitor (PCI) has been found in the prostate and possibly is a marker to distinguish normal prostate, benign prostatic hyperplasia, and prostate cancer. In this study, we assessed PCI expression in normal, hyperplastic, and malignant prostatic tissues, prostate cancer cell lines, and the CWR22 pros...

The serine protease inhibitor (serpin) protein C inhibitor (PCI; also named plasminogen activator inhibitor-3) regulates serine proteases in hemostasis, fibrinolysis, and reproduction. The biochemical activity of PCI is not fully defined partly due to the lack of a convenient expression system for active rPCI. Using pET-15b plasmid, Ni(2+)-chelate...

We report the identification and functional analysis of a type II transmembrane serine protease encoded by the mouse differentially expressed in squamous cell carcinoma (DESC) 1 gene, and the definition of a cluster of seven homologous DESC1-like genes within a 0.5-Mb region of mouse chromosome 5E1. This locus is syntenic to a region of human chrom...

The serine protease inhibitor (serpin), plasminogen activator inhibitor-1 (PAI-1) rapidly inactivates tissue plasminogen activator (tPA) and urokinase plasminogen activator to prevent plasminogen activation to plasmin. Although PAI-1 is a major regulator of fibrinolysis, PAI-1 also has a role in regulating coagulation due to its ability to inhibit...

We used 55 Ala-scanned recombinant thrombin molecules to define residues important for inhibition by the serine protease inhibitor (serpin) heparin cofactor II (HCII) in the absence and presence of glycosaminoglycans. We verified the importance of numerous basic residues in anion-binding exosite-1 (exosite-1) and found 4 additional residues, Gln24,...

Factor (F)Xa has 11 gamma-carboxylated glutamic acid (Gla) residues that are involved in calcium-dependent membrane binding. The serpin antithrombin (AT) is an important physiological regulator of FXa activity in an inhibition reaction that is enhanced by heparin. Recently, Rezaie showed that calcium further enhanced the heparin-catalyzed AT inhibi...

We studied the RNA aptamer Toggle-25/thrombin interaction during inhibition by antithrombin (AT), heparin cofactor II (HCII) and protein C inhibitor (PCI). Thrombin inhibition was reduced 3-fold by Toggle-25 for AT and HCII, but it was slightly enhanced for PCI. In the presence of glycosaminoglycans, AT and PCI had significantly reduced thrombin in...

Urokinase-type (uPA) plasminogen activator is regulated by serine protease inhibitors (serpins), especially plasminogen activator inhibitor-1 (PAI-1). In many cancers, uPA and PAI-1 contribute to the invasive phenotype. We examined the in vitro migration and invasive capabilities of breast, ovarian, endometrial, and cervical cancer cell lines compa...

One of the more common features of serpins is the ability to bind various ligands. Ligand binding can occur so that the inhibitory properties of the serpin are regulated, so that the serpin can be localized, or to produce or modulate some other biological function of the serpin. Ligands known to affect serpin biologic activity include glycosaminogl...

The physiologic function of the serpin heparin cofactor II (HCII) is not fully understood. We have hypothesized that HCII functions as an extravascular inhibitor of thrombin. Thrombin formed at a site of injury has been hypothesized to contribute to migration and proliferation of fibroblasts and smooth muscle cells involved in wound healing. To beg...

The role of lysines 37-39 (chymotrypsin numbering) in the 37-loop of the serine protease activated protein C (APC) was studied by expressing acidic and neutral recombinant APC (rAPC) mutants. Activity of the APC mutants was assessed using human plasma and plasma-purified and recombinant derivatives of protein C inhibitor (PCI; also known as plasmin...

The role of lysines 37–39 (chymotrypsin numbering) in the 37-loop of the serine protease activated protein C (APC) was studied by expressing acidic and neutral recombinant APC (rAPC) mutants. Activity of the APC mutants was assessed using human plasma and plasma-purified and recombinant derivatives of protein C inhibitor (PCI; also known as plasmin...

The interaction of lactoferrin with endogenous heparin-like molecules modulates glycosaminoglycan-mediated biological processes. We performed site-specific mutagenesis and expressed recombinant lactoferrin and lactoferrin mutants by the baculovirus insect cell expression system. Five basic residues at the lactoferrin N terminus; Arg 5, Arg 25, Arg...

Plasminogen activator inhibitor-1 (PAI-1), an inhibitor of urokinase plasminogen activator, is paradoxically associated with a poor prognosis in breast cancer. PAI-1 is linked to several processes in the metastatic cascade. However, the role of PAI-1 in metastatic processes, which may be independent of protease inhibitory activity, is not fully und...

The serine proteases sequentially activated to form a fibrin clot are inhibited primarily by members of the serpin family, which use a unique beta-sheet expansion mechanism to trap and destroy their targets. Since the discovery that serpins were a family of serine protease inhibitors there has been controversy as to the role of conformational chang...

Antithrombin (ATIII), heparin cofactor II (HCII) and protein C inhibitor (PCI; also named plasminogen activator inhibitor-3) are serine protease inhibitors (serpins) whose thrombin inhibition activity is accelerated in the presence of glycosaminoglycans. We compared the inhibition properties of PCI and HCII to ATIII using R93A/R97A/R101A thrombin,...

The protein C/protein S system is known to regulate thrombin generation in vivo by cleaving factors Va and VIIIa. We have examined the activity of activated protein C in several tissue factor-initiated models of coagulation. We used 4 models: monocytes as the tissue factor source with platelets as the thrombin-generating surface; endothelial cells...

We used site-directed mutagenesis to investigate the role of Glu(69), Asp(70), Asp(71), Asp(72), Tyr-sulfate(73), and Asp(75) in the second acidic region (AR2) of the serpin heparin cofactor II (HCII) during formation of the thrombin.HCII complex with and without glycosaminoglycans. E69Q/D70N/D71N recombinant (r)HCII, D72N/Y73F/D75N rHCII, and E69Q...

Serpins are a class of proteins involved in the regulation of serine and other types of proteases. In humans, the majority of serpins regulate the functions of proteases involved in the body's response to injury. This includes roles in coagulation, fibrinolysis, inflammation, wound healing, and tissue repair. Serpins have been implicated in various...