Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tissue Inhibitor of Metalloproteinase

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101950

Synonyms

Historical Background

In mammals, the tissue inhibitor of metalloproteinase (TIMP) family is comprised of four members, TIMP1-4. TIMPs are the primary inhibitors of metalloproteinases, such as the matrix metalloprotease (MMP) family, a disintegrin and metalloproteinase (ADAM) family, and the ADAMs with thrombospondin motifs (ADAMTS) family (Brew and Nagase 2010). TIMPs range in size from 22 to 28 kDA and are variably glycosylated (Murphy 2011). Further, each TIMP contains two distinct domains, an N-terminal and C-terminal domain of ∼125 and 65 amino acids, respectively, connected through six conserved disulfide bonds (Brew and Nagase 2010; Murphy 2011). Each of these domains has critical roles in controlling TIMP function and localization.

The N-terminal domain, which folds independently and is composed of three α helices and five β strands arranged in a twisted β barrel, is critical for the inhibition of metalloproteinase activity (Murphy 2011). Specifically, the N-terminal domain interacts with the active site of metalloproteinases, like a wedge, in a 1:1 stoichiometric enzyme-inhibitor complex (Murphy 2011). The N-terminal domain also mediates TIMP affinity for metalloproteinases. For example, the N-terminal domain of TIMP3 has been found to interact with regions of the C-terminal domains of ADAMTS4 and ADAMTS5 promoting interaction between the enzyme and inhibitor (Brew and Nagase 2010).

The C-terminal domain of TIMPs has been found to mediate additional protein-protein interactions. By binding to latent MMPs, TIMPs have been found to regulate MMP activation. Specifically, the C-terminal domain of TIMP1 and TIMP2 can bind latent MMP9 and latent MMP2, respectively (Murphy 2011). The C-terminal domain in both TIMP1 and TIMP3 also mediate non-metalloproteinase-dependent protein-protein interactions. Specifically, TIMP1 binds to the cell surface of human breast epithelial cells via its C-terminal domain, potentially through interaction with β1 integrin, and this interaction is associated with reduced mammary epithelial cell apoptosis (Chirco et al. 2006). Additionally, TIMP3 binds to the extracellular matrix (ECM), specifically via interactions with sulfated proteoglycans (Stetler-Stevenson 2008). Importantly, this interaction with sulfated proteoglycans makes TIMP3 unique as it localizes TIMP3 to the ECM, whereas TIMP1, TIMP2, and TIMP4 are generally considered to be soluble (Stetler-Stevenson 2008).

TIMP Localization and Expression

TIMPs are constitutively expressed in many mammalian tissues. Additionally, TIMP expression is also induced or inhibited under certain conditions (i.e., during development, following injury or infection, etc.) with the exact role (i.e., beneficial or detrimental) dependent on the specific TIMP and tissue being examined. These changes in TIMP expression are regulated at the transcriptional level by cytokines, growth factors, and microRNAs (miRNAs) (Murphy 2011). Further, TIMP levels in plasma or tissue from patients with different diseases have been used as biomarkers and to correlate with the type and stage of diseases (Lorente et al. 2014; Westhoff et al. 2015).

TIMP1

TIMP1 is expressed in many tissues, but most prominently in the lungs, bone, and reproductive organs, and this expression can be stimulated by serum, phorbol esters, cytokines, growth factors, and viruses (Stetler-Stevenson 2008; Chirco et al. 2006). For example, TIMP1 has been shown to be upregulated by pro-inflammatory cytokines such as tumor necrosis factor α (TNFα), transforming growth factor β (TGFβ), and interleukin 1β (IL1β) (Chirco et al. 2006).

Within inflamed or injured tissue, TIMP1 expression is generally increased relative to healthy tissue, as well as in comparison to expression of other TIMPs. For example, TIMP1 expression is increased in the lung epithelium following injury (Chen et al. 2008). TIMP1 expression is also increased in Dupuytren’s disease and chronic kidney disease (i.e., tubulointerstitial fibrosis and glomerulosclerosis) (Brew and Nagase 2010). Additionally, TIMP1 levels in the serum have been found to be prognostic in severe sepsis with increased TIMP1 associated with enhanced mortality (Lorente et al. 2014).

TIMP2

TIMP2 is constitutively expressed within many different mammalian tissues. However, while primarily constitutively expressed, TIMP2 expression can be modified by multiple factors, including cytokines, growth factors, hormones, and bacteria (Murphy 2011). For example, TIMP2 expression can be upregulated by retinoic acid in endothelial cells and by lipopolysaccharide (LPS) in macrophages (Fassina et al. 2000). TIMP2 expression is downregulated, however, by an increase in tissue plasminogen activator (tPA), TNFα, and TGFβ (Fassina et al. 2000). TIMP2 production is also reduced in human breast cancer cells after hormonal treatment with progestin or a combination of progestin and estradiol (Fassina et al. 2000).

TIMP2 expression has also been found to change within the setting of inflammation and injury; however, this change in expression, and specifically whether TIMP2 is upregulated or downregulated, is dependent on the tissue and type of injury. For example, TIMP2 mRNA and protein expression has been found to be directly controlled by miR761 in non-small cell lung cancer (NSCLC) tumors. Specifically, increased miR761 decreases TIMP2 expression leading to increased NSCLC proliferation and metastasis (Yan et al. 2015). However, TIMP2 expression is significantly increased in the urine of neonatal and pediatric patients with acute kidney injury (Westhoff et al. 2015). Further, urinary TIMP2 levels combined with insulin-like growth factor (IGF)-binding protein 7 levels have been found to have good diagnostic performance in predicting adverse outcomes in these patients (Westhoff et al. 2015).

TIMP3

TIMP3 is expressed in many tissues including the lung, heart, kidney, and thymus and is tightly regulated during proliferation, differentiation, and senescence (Stetler-Stevenson 2008). Regulation of TIMP3 expression is mediated by growth factors and cytokines, such as TNFα and TGFβ, and general transcriptional modifications such as promoter methylation and S-nitrosylation attenuate TIMP3 expression (Murphy 2011). Importantly, unlike other TIMP family members, which are considered to be soluble, TIMP3 protein is known to be localized to the ECM (Murphy 2011). Further, TIMP3 bioavailability is regulated by the scavenger receptor low-density lipoprotein receptor-related protein 1 (LRP1), which binds to extracellular TIMP3 and facilitates endocytosis into the cell (Khokha et al. 2013).

TIMP3 expression has also been found to vary following tissue injury/infection. For example, TIMP3 is expressed at high levels within the lung; however, following bleomycin-induced lung injury, expression decreases rapidly (Gill et al. 2010). Further, one of the cell types expressing TIMP3 within the lung are the microvascular endothelial cells; however, TIMP3 expression within these cells is significantly reduced under pro-inflammatory (septic) conditions. TIMP3 expression has also recently been shown to be regulated by miRNAs. Specifically, TIMP3 appears to be regulated by miR21 as increased miR21 in melanoma cells decreases TIMP3 expression (del Campo et al. 2015).

Loss of TIMP3 expression appears to primarily be associated with augmented inflammation. Specifically, increased inflammation has been observed in the lungs, heart, liver, kidney, and joints in a variety of injury models in mice lacking TIMP3 (Khokha et al. 2013). This increased inflammation has been associated, at least in the lungs, with altered macrophage function. Further, loss of TIMP3 in melanoma cells is associated with increased cell invasiveness (del Campo et al. 2015).

TIMP4

TIMP4 is the least studied of all the TIMPs. TIMP4 expression is primarily restricted to the heart, kidney, and, to a lesser extent, ovaries (Stetler-Stevenson 2008). While the upregulation of TIMP1 is used as a biomarker in many diseases, TIMP4 expression is heavily reduced in many central nervous system (CNS) diseases. TIMP4 expression is also altered in various types of cancer: it is elevated in papillary cancer cells, but reduced in clear cell carcinoma (Melendez-Zajgla et al. 2008).

Metalloproteinase-Dependent Signaling by TIMPs

The most studied role for TIMPs, and often considered their primary function, is the ability to inhibit metalloproteinases. Metalloproteinases, which have a critical role in processing (cleavage and degradation) a variety of extracellular proteins, are endopeptidases requiring a metal ion – primarily Zn2+, but in some cases Ca2+ − in their active site (Khokha et al. 2013). There are many different families of metalloproteinases, but, with respect to TIMPs, the most notable are the MMPs and ADAMs.

There are over 25 different MMPs in mammals, all of which include three common domains: a signal peptide, a pro-peptide region, and a catalytic region (Khokha et al. 2013). Additionally, most MMPs also contain a hemopexin-like C-terminal region, which is connected to the catalytic region by a short, flexible hinge (Khokha et al. 2013). Some MMPs are synthesized in their active form, while others are secreted as inactive (latent) proteins, or zymogens, and are maintained in this inactive conformation through an interaction between a cysteine residue in the pro-peptide domain and the metal ion in the active site of the catalytic region (Brew and Nagase 2010). Once the pro-peptide domain has been cleaved from latent MMPs, the cysteine residue is removed and the metal ion can interact with substrates (Chirco et al. 2006).

Most ADAMs contain both a catalytic domain, which includes a Zn2+ binding site, and a pro-peptide domain (Edwards et al. 2008). Additionally, ADAMs contain a disintegrin-binding domain, which mediates interaction with the ECM, a C-terminal cytoplasmic tail, and a transmembrane region (Edwards et al. 2008). Interestingly, of the 25 human ADAMs, only 13 are considered functional proteases; 4 are considered to be pseudogenes, while the remaining 8 are believed to be involved in mediating protein-protein interactions (Edwards et al. 2008).

All four TIMPs share similar structural properties, and in vitro studies have demonstrated overlapping metalloproteinase inhibition profiles (i.e., which metalloproteinases each TIMP inhibits); however, there are differences that exist between each TIMP in their ability to inhibit specific metalloproteinases. For example, TIMP1 does not appear to be an effective inhibitor of the membrane-type MMPs (MT-MMPs; MMP14, MMP15, MMP16, MMP17, MMP24, and MMP26) (Murphy 2011). Additionally, TIMP3 is unique from other TIMPs as it is a very strong inhibitor of ADAMs and, currently, is the only known inhibitor of ADAMTSs (Murphy 2011). In addition to inhibiting MMPs, TIMPs have also been linked to MMP activation through interaction with latent MMPs. Presently, it is known that latent MMP2 can bind TIMP2, TIMP3, and TIMP4 and latent MMP9 can bind TIMP1 and TIMP3 (Murphy 2011). However, the best characterized of these interactions is the latent MMP2/TIMP2 interaction (Fig. 1). Specifically, TIMP2 binds MMP14 on the cell surface to form a receptor for latent MMP2. This bound MMP2 is then activated through cleavage of the pro-domain by another free MMP14 (Khokha et al. 2013). Interestingly, the interaction between MMP2 and TIMP2 appears to be concentration dependent. When TIMP2 is present in low concentrations, it appears to be involved primarily in MMP2 activation; however, when TIMP2 is present at high concentrations, it acts as an MMP2 inhibitor (Khokha et al. 2013).
Tissue Inhibitor of Metalloproteinase, Fig. 1

Model of proMMP2 activation by MMP14 and TIMP2. (a) The N-terminus of TIMP2 binds to the catalytic domain of active MMP14. (b) The C-terminus of TIMP2 then binds the C-terminus of latent MMP2. (c) The pro-peptide domain of MMP2 is cleaved by a second nearby MMP14 and the active MMP2 is released

Importantly, MMPs degrade different components of the ECM including collagens, gelatin, fibronectin, laminin, and elastin, which mediates cell-ECM interaction and downstream signaling through integrins; release of cryptic ECM fragments, which activate cell signaling; and release of sequestered growth factors (Gill et al. 2006; Khokha et al. 2013). In addition, MMPs are involved in regulation of other cell signaling pathways through chemokine processing leading to activation and degradation of the chemokines, as well as activation of growth factors such as TGFβ (Khokha et al. 2013). Further, ADAMs, which are described as “sheddases,” can mediate cell signaling by cleaving various cytokines and cytokine receptors from the cell surface (Edwards et al. 2008). Thus, TIMP regulation of metalloproteinase activity regulates many different signaling mechanisms (Fig. 2, Table 1). Specific examples of these functions are provided below for each TIMP.
Tissue Inhibitor of Metalloproteinase, Fig. 2

Tissue inhibitors of metalloproteinases (TIMPs) mediate cell signaling both indirectly (through metalloproteinase-dependent mechanisms) and directly (through metalloproteinase-independent mechanisms) in multiple cell types, including endothelial cells. Metalloproteinase-dependent signaling includes (a) cleavage of the extracellular matrix (ECM) leading to modified cell-ECM interaction and release of cryptic ECM fragments, (b) shedding of leukocyte receptors leading to impaired leukocyte adhesion to the cell surface, and (c) cleavage of cytokines/growth factors and their cell surface receptors attenuating downstream signaling pathways. Metalloproteinase-independent signaling includes the following: (d) TIMPs block ligand-receptor interactions, inhibiting signaling cascades (e.g., TIMP3 inhibition of vascular endothelial growth factor (VEGF)-VEGF receptor binding), and (e) TIMPs directly bind to receptors activating signaling cascades (e.g., TIMP1 binds CD63)

Tissue Inhibitor of Metalloproteinase, Table 1

Tissue inhibitors of metalloproteinases (TIMPs) regulate signaling pathways via metalloproteinase-dependent and metalloproteinase-independent mechanisms

Metalloproteinase-dependent function

TIMP1

TIMP2

TIMP3

TIMP4

MMP inhibition

+

++

++

+

ADAM inhibition

+/−

+/−

++

+/−

MMP activation

+

+

  

Inhibits ECM degradation

+

+

+

+

Inhibits inflammatory cell recruitment

++

+

++

 

Inhibits growth factor release/activation

+

+

+

 

Maintains cell-cell interaction

  

+

 

Promotes cell proliferation

+

+

+

 

Inhibits cell proliferation

 

+

+

 

Anti-angiogenic

+

+

  

Pro-apoptotic

+

 

+

 

Anti-apoptotic

+

   

Metalloproteinase-independent function

Inhibits tumor progression

+

+

  

Cell proliferation

+

+

+

 

Cell growth inhibition

+

+

+

 

Cell migration

 

+

  

Anti-angiogenic

  

+

 

Pro-apoptotic

  

+

 

Anti-apoptotic

+

  

+

TIMP1

TIMP1 has been found to promote cell survival by reducing apoptosis. This is thought to be at least partially dependent on inhibition of MMPs and subsequent ECM degradation as a mutation of TIMP1 that conferred selective MMP inhibition blocked this anti-apoptotic activity in hepatic stellate cells (Chirco et al. 2006). TIMP1 has also been shown to regulate cell growth by MMP inhibition. In a mouse liver regeneration model, TIMP1 reduced hepatocyte cell proliferation by inhibition of MMP-mediated activation of hepatocyte growth factor (Chirco et al. 2006). TIMP1 also inhibited liver hyperplasia by reducing the levels of bioactive IGF II via inhibition of MMP-mediated degradation of IGF-binding protein (Chirco et al. 2006). Additionally, TIMP1 has been found to mediate bronchiole epithelial cell migration following injury, likely through regulation of syndecan-1 shedding by MMP7 (Chen et al. 2008).

TIMP2

Angiogenesis, which is mediated by multiple signaling pathways, is at least partly regulated by TIMP2 (Brew and Nagase 2010). TIMP2 also mediates syndecan-1 cleavage from the cell surface leading to decreased cell migration (Endo et al. 2003). This is demonstrated by the addition of TIMP2 or the synthetic MMP inhibitor, BB-94, which impairs migration of HT1080 fibrosarcoma cells through inhibition of MMP14 cleavage of syndecan-1 from the cell surface leading to an accumulation of cell-surface-associated syndecan-1 (Endo et al. 2003).

TIMP3

Similar to TIMP1, TIMP3 regulates apoptosis; however, TIMP3 has been found to promote apoptosis. This ability to promote apoptosis is dependent on the N-terminal domain, which is required for metalloproteinase inhibition (Brew and Nagase 2010). Specifically, TIMP3 inhibits metalloproteinase-dependent shedding of death receptors (e.g., FAS) from the cell surface, thereby promoting ligand-receptor interaction and activation of apoptosis signaling pathways (Brew and Nagase 2010). TIMP3 also has the distinct ability to inhibit the majority of ADAMs (Edwards et al. 2008). ADAM17, also known as TNFα-converting enzyme (TACE), cleaves both TNFα and the TNFα receptor (TNFR1) from the cell surface, thereby acting to promote TNFα signaling but also restrict it. TIMP3 is considered the primary endogenous inhibitor of ADAM17 as loss of TIMP3 is associated with excessive shedding of TNFα and TNFR1 in many different injury models (Khokha et al. 2013).

TIMP3 also mediates cell signaling through control of ECM degradation. Specifically, TIMP3 inhibits metalloproteinase-dependent fibronectin degradation during development of the lungs (e.g., during formation of the airways), which promotes cell-ECM interaction and the phosphorylation of focal adhesion kinase leading to cell proliferation (Gill et al. 2006).

TIMP4

Relative to other TIMPs, little is known about TIMP4. However, there is indirect evidence that TIMP4 may be involved in mediating cell signaling following injury through metalloproteinase-dependent mechanisms. Specifically, TIMP4 expression is decreased in the myocardium following ischemia/reperfusion, and this is associated with increased MMP14 activity and enhanced inflammation (Takawale et al. 2014). Further, in mice completely lacking TIMP4, both the increased MMP14 activity and inflammation persist following ischemia reperfusion suggesting a critical role for TIMP4 in regulation of MMP14 activity and subsequent, pro-inflammatory signaling (Takawale et al. 2014). The specific signaling pathway mediated by TIMP4 inhibition of MMP14, however, remains to be determined.

Metalloproteinase-Independent Signaling by TIMPs

Over the past 20 years, TIMPs have been found to exert control over diverse biological processes through mechanisms independent of metalloproteinase inhibition (Fig. 2, Table 1). These processes include cell growth, migration, apoptosis, and angiogenesis. The metalloproteinase-independent functions of TIMP1 and TIMP2 are the most characterized; however, recently, a number of studies have demonstrated critical metalloproteinase-independent functions for TIMP3.

TIMP1

Following the initial identification and characterization of TIMP1, it was determined that it was identical to a factor with erythroid-potentiating activity (EPA), which supports the growth of erythroid precursors (Jung et al. 2006). Subsequently, TIMP1 has been shown to induce proliferation in keratinocytes, fibroblasts, and metanephric mesenchymal cells during nephron morphogenesis (Stetler-Stevenson 2008). Moreover, mutated TIMP1 lacking the ability to inhibit metalloproteinases retained this cell growth-promoting activity, confirming that TIMP1 mediated cell proliferation through a metalloproteinase-independent mechanism (Brew and Nagase 2010). Further, TIMP1 was found to promote cell proliferation through activation of several signaling pathways, including the tyrosine kinase/mitogen-activated protein kinase (MAPK) pathway, which led to increased Ras-guanosine-5′-triphosphate (GTP) (Brew and Nagase 2010).

Interestingly, the effect of TIMP1 on cell growth is dependent on cell type as TIMP1 overexpression in human breast epithelial (MCF10A) cells leads to cell cycle arrest in G1, as well as cell growth inhibition due to downregulation of cyclin D1, upregulation of the cyclin-dependent kinase inhibitor p27Kip1, and hypophosphorylation of retinoblastoma (RB) (Brew and Nagase 2010). However, while growth was inhibited in cells overexpressing TIMP1, the cells remained viable, even under G1 arrest, suggesting TIMP1 promotes cell survival (Brew and Nagase 2010)

CD63, a protein in the tetraspanin family, has been identified as a potential cell surface receptor for TIMP1 (Brew and Nagase 2010). Overexpression of CD63 and TIMP1 in human mammary epithelial cells disrupts acinar formation and inhibits apoptosis (Jung et al. 2006). Further, downregulation of CD63 blocks TIMP1 binding to the cell surface and restores acinar formation and apoptosis (Jung et al. 2006). Other studies have demonstrated that CD63 is linked to the phosphoinositide 3-kinase (PI3K), focal adhesion kinase (FAK), proto-oncogene tyrosine-protein kinase (Src), and protein kinase B (Akt) signaling pathways, which provides further support for a strong role of TIMP1 in the regulation of cell survival/proliferation through control of multiple signal transduction pathways (Jung et al. 2006). Importantly, CD63 does not interact with TIMP2 or TIMP3, suggesting that TIMPs may have specific receptors (Jung et al. 2006).

TIMP2

TIMP2 has also been observed to have EPA (Brew and Nagase 2010). Further, TIMP2 has also been shown to promote keratinocyte, fibroblast, and metanephric mesenchymal cell proliferation. Similar to TIMP1, TIMP2 has been found to increase the level of Ras-GTP, but does so via protein kinase A (PKA) activation, which is directly involved in Ras/PI3K complex formation. While TIMP1 is also linked to the PI3K pathway, TIMP1 regulation of PI3K is dependent on CD63. TIMP2, however, binds to integrin α3β1, leading to cell proliferation (Kim et al. 2015). TIMP2 binding to α3β1 also regulates FAK, Akt, and extracellular signal-regulated kinase (ERK) 1/2 activation (Chirco et al. 2006; Kim et al. 2015).

Additionally, TIMP2 has been found to regulate angiogenesis through multiple pathways. Overexpression of TIMP2 inhibits tumor growth and angiogenesis by upregulating MAP kinase phosphatase 1, which dephosphorylates p38 MAPK, a kinase involved in endothelial cell proliferation and migration (Brew and Nagase 2010). Further, treatment of human microvascular endothelial cells with a TIMP2 analogue lacking MMP inhibitory activity blocks endothelial cell proliferation and angiogenesis by inhibiting vascular endothelial growth factor (VEGF)-mediated receptor (VEGFR) 2 phosphorylation and, subsequently, disrupting the associated downstream activation of phospholipase C, Ca2+ flux, Akt, and endothelial nitric oxide synthase (eNOS) (Stetler-Stevenson 2008). Finally, TIMP2 is the only TIMP to inhibit fibroblast growth factor 2 (FGF2)-stimulated proliferation of human endothelial cells, which also inhibits angiogenesis (Seo et al. 2006). This phenomenon was only observed with free TIMP2, and not with TIMP2 bound to latent MMP2. Further, the ability of TIMP2 to inhibit angiogenesis through cell cycle arrest is metalloproteinase independent as addition of synthetic MMP inhibitors did not mimic the effects (Seo et al. 2006).

TIMP3

TIMP3 has recently been found to have metalloproteinase-independent roles regulating cell proliferation and cell survival. Specifically, TIMP3 inhibits cell proliferation. For example, TIMP3 binds directly to VEGFR2 on endothelial cells and blocks VEGF-VEGFR2 interaction, thereby inhibiting phosphorylation of VEGFR2 and downstream signaling leading to decreased endothelial cell proliferation (Brew and Nagase 2010). Further, VEGFR2 activation in response to VEGF was also reduced by overexpression of a mutant TIMP3 that lacked the ability to inhibit MMPs suggesting that TIMP3 inhibition of VEGF signaling is a metalloproteinase-independent function (Brew and Nagase 2010). Similarly, TIMP3 also binds the angiotensin (ANG) II type 2 receptor, and overexpression of both TIMP3 and the ANG II type 2 receptor inhibits human umbilical vein endothelial cell proliferation and angiogenesis through inhibition of Akt and eNOS (Stetler-Stevenson 2008).

TIMP4

At present, TIMP4 metalloproteinase-independent functions are not well understood. There is putative evidence that, similar to TIMP1, TIMP4 may interact with CD63. This TIMP4-CD63 interaction appears to activate β1 integrin signaling, thereby promoting activation of survival signaling pathways such as FAK, Src, PI3K, and MAPK; however, this has yet to be demonstrated conclusively (Melendez-Zajgla et al. 2008).

Summary

TIMPs, once thought to simply regulate the activity of metalloproteinases, are much more complex than initially imagined. Specifically, they are integral regulators of molecular signaling pathways through both metalloproteinase-dependent and metalloproteinase-independent mechanisms. Importantly, there is also great potential for the application of TIMPs as therapeutic tools for many different diseases, especially with the development of engineered TIMPs that display altered specificity for individual metalloproteinases as well as those that allow for the differentiation between the metalloproteinase-dependent and metalloproteinase-independent functions.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Centre for Critical Illness ResearchLawson Health Research InstituteLondonCanada
  2. 2.Division of RespirologySchulich School of Medicine and Dentistry, Western UniversityLondonCanada
  3. 3.Department of MedicineSchulich School of Medicine and Dentistry, Western UniversityLondonCanada
  4. 4.Department of Physiology and PharmacologySchulich School of Medicine and Dentistry, Western UniversityLondonCanada