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Laurianne Van Landeghem

Asst Professor

CVM Main Building D329

Publications

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Grants

Date: 06/01/22 - 5/31/25
Amount: $640,000.00
Funding Agencies: US Dept. of Agriculture - National Institute of Food and Agriculture (USDA NIFA)

Our long-term goal is to understand the interplay between nutrition and gut health in order to address major early life intestinal health issues of swine. In preliminary studies, recovery of injured mucosa was impaired in suckling versus weanling pigs, and we have linked this to an underdeveloped component of the enteric nervous system, the enteric glial cell network. This has led us to investigate oligosaccharides, which we have shown alter the microbiome to induce maturation of enteric neural elements involved in gut barrier function. Our central hypothesis is that creep feeding oligosaccharides to suckling pigs will accelerate postnatal microbial colonization, thereby enhancing glial cell maturation and reducing inflammation to promote efficient intestinal barrier maintenance and repair in the peri-weaning period in response to the health challenges of ischemic injury (suckling piglets) or weaning stress (weanling pigs). Our specific objectives are: 1) Determine the ability of creep fed prebiotic oligosaccharides to accelerate postnatal microbial colonization, hasten the development of the EGC network, and enhance intestinal barrier function; 2) Determine if supplementation of creep fed prebiotic oligosaccharides hastens recovery of mucosal barrier function in ischemic-injured suckling intestine by stimulating EGC-regulated restitution; 3) Determine if supplementation of prebiotic oligosaccharides reduces the impact of weaning stress on mast cell infiltration, intestinal health, and growth performance. This work is applicable to the swine industry using a commercial creep feeding system. Our studies will assess intestinal health using state-of-the-art electrophysiologic, cellular, and immunolabeling approaches to define response of the gut to injury and stress.

Date: 02/01/23 - 1/31/25
Amount: $37,172.00
Funding Agencies: American Kennel Club Canine Health Foundation, Inc.

Mucocele formation is the most common gallbladder disease to afflict dogs. Despite the best surgical care, 17% will not survive. Retrospective studies alone report numbers of affected dogs in the thousands and over 80 publications have now addressed this specific disease. We don’t know what causes mucocele formation and have no way to predict, prevent, or reverse the epidemic rise in suffering and lost lives of these dogs. The long-range goal of our research is to identify the cause of mucocele formation in dogs. The objective of this study is to investigate a specific xenobiotic exposure that we identified in dogs with mucocele formation, for its potential to be the underlying cause of this disease. Our hypothesis is that the discovered compound will be sufficient to inhibit fluid secretion and promote abnormal mucus formation by canine gallbladder epithelial cells; mechanisms that are consistent with an ability to promote mucocele formation in dogs. To test this hypothesis, we developed methods for culture of 3D “mini-gallbladder” organoids from a single canine gallbladder for use as a model for studying mucocele formation. Our proposal aims are to determine if the discovered compound is sufficient to inhibit fluid secretion and/or promote accumulation of abnormal mucus secretions by canine gallbladder organoids. If the discovered compound mediates these mucocele-promoting effects, these studies will have identified the most probable cause of mucocele formation in dogs. This outcome is expected to have a significant impact on a prevalent problem by enabling veterinarians to prevent and treat this disease.

Date: 04/01/23 - 3/31/24
Amount: $340,292.00
Funding Agencies: National Institutes of Health (NIH)

Resistance to anti-cancer therapies largely explains the catastrophic 5-year survival rate of patients with advanced colon cancer. Traditional chemotherapy regimens have been designed to efficiently stop proliferation and initiate apoptosis in cancer cells, but fail to appreciate the pro-chemoresistance signals emanating from cells surrounding the tumor. We have recently identified a novel cellular component of the tumor microenvironment: the enteric glial cells (EGC). We and others have shown over the last 15 years that EGC are potent inducers of barrier function and healing in a healthy colon. Recently we have demonstrated that the EGC network substantially infiltrates human colon adenocarcinomas and promotes cancer stem cell tumor-forming abilities via a paracrine PGE2-EP4 pathway. Nevertheless, whether EGC impact colon cancer resistance to chemotherapy remains unknown. Our preliminary studies indicate that EGC protect cancer stem cells against apoptosis induced by chemotherapeutic drugs, allowing for enhanced tumor formation and growth despite the chemotherapy treatment. We also have evidence that this is (1) dependent on activation of the MRN-ATM pathway -which plays a central role in DNA repair- in cancer cells and (2) exacerbated by EGC activation with chemotherapy. Using mass spectrometry analyses, we have identified FSTL3 as a novel EGC-derived factor and generated preliminary results implicating FSTL3 in EGC chemoprotective effects. Therefore, we propose to test the hypothesis that “in response to chemotherapeutic drugs, EGC release FSTL3 in the tumor microenvironment, which enhances cancer stem cell chemoresistance and allows for tumor formation and growth by promoting DNA repair driven by the MRN-ATM pathway”. Specific Aim #1 will determine whether EGC promote cancer stem cell resistance to chemotherapies via the release of FSTL3. Specific Aim #2 will test whether EGC protective effects are mediated by increased DNA repair as a result of activation of the MRN-ATM pathway. Specific Aim #3 will determine whether blocking FSTL3 production in EGC sensitizes colon tumors to chemotherapies in vivo. Studies will use translationally relevant primary cultures of human EGC and cancer cells, 3D co-culture platforms, orthotopic co-engraftment in immunodeficient mice, murine models of colon carcinogenesis, transgenic mice allowing for chemogenetic activation of EGC (GFAP-hM3Dq) and inducible gene targeting in EGC (GFAP-CreERT2), in addition to cutting-edge molecular profiling using single cell RNA seq and mass spectrometry studies to identify the pro-chemoresistance factor(s) (and in particular FSTL3) and pathway(s) involved. These studies will not only improve our understanding of the cellular and molecular mechanisms driving colon cancer chemoresistance but will also demonstrate the therapeutic potential of developing strategies combining targeted therapies against EGC-derived FSTL3 and traditional chemotherapy regimens.

Date: 08/15/19 - 6/30/23
Amount: $1,465,140.00
Funding Agencies: National Institutes of Health (NIH)

Breaches in the intestinal barrier lead to sepsis and death if epithelial coverage is not rapidly restored, particularly in neonates. The reason for higher mortality in infants with intestinal injury has not been explained. High infant mortality results from diseases associated with ischemia/ reperfusion (I/R) injury, including necrotizing enterocolitis. Animals also suffer from diseases marked by epithelial sloughing and high mortality, including PED virus in suckling piglets. In juvenile pigs, we have studied rapid intestinal repair by epithelial cell migration (restitution). However, in preliminary studies, we have shown an age-dependent deficiency in the recovery of barrier function following ischemic injury with a near-total lack of restitution in suckling neonates. This is associated with an immature enteric glial cell (EGC) network, which has recently been shown to play a pivotal role in intestinal regeneration. We have also shown positive changes in the microbiome in response to supplementing formula with oligosaccharides. Our central hypothesis is that intestinal repair of ischemic injury is deficient in neonates as a result of a failure of epithelial restitution, which can be rescued by paracrine signaling from maturation of the EGC network in response to a microbiome conditioned by increasing nutritional oligosaccharides. We will test this hypothesis with the following specific aims: 1) Determine age-dependent differences in the EGC network and its paracrine factors in normal and I/R-injured porcine mucosa; 2) Rescue neonatal I/R-injured intestinal mucosa with exogenous application of species-specific EGC soluble factors; 3) Increase EGC numbers and paracrine factors by delivering increased nutritional oligosaccharides to the gut. To examine these specific aims, we will use our unique age-dependent porcine model of mucosal repair, primary culture of porcine EGC, and state of the art imaging techniques for glial cells, including immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO). Additionally, we will deliver oligosaccharide-fortified formula with high throughput screening of the microbiome in conjunction with analyses of the EGC network. We expect to identify nutritionally rescuable deficiencies in EGC-directed mechanisms of intestinal recovery.

Date: 04/01/19 - 3/31/23
Amount: $499,999.00
Funding Agencies: US Dept. of Agriculture - National Institute of Food and Agriculture (USDA NIFA)

Our long-term goal is to understand the interplay between nutrition and gut health using a porcine model of ischemic intestinal injury to investigate mechanisms of mucosal repair. In preliminary studies, we have shown that dietary provision of arachidonate (ARA) to neonates with ischemic intestinal injury hastens repair. Nonetheless, recovery of injured mucosa remains markedly impaired in neonates compared to juvenile animals. This led us to investigate oligosaccharides, which alter the microbiome to induce maturation of enteric neural elements involved in gut barrier function. Our central hypothesis is that intestinal repair of ischemic injury in porcine neonates can be synergistically rescued by a combination of (1) dietary oligosaccharides, that will interact with the microbiome to accelerate development of the mucosal EGC network and thus increase the bioavailability of glial-derived pro-reparative factors, and (2) ARA-derived eicosanoids which will augment closure of interepithelial tight junctions within restituting epithelium. Our specific objectives are: 1) Determine the ability of fed oligosaccharides to induce structural changes in enteric microbial communities that hasten the development of the EGC network; and 2) Determine if supplementation of oligosaccharides and ARA synergistically hastens recovery of mucosal barrier function in ischemic-injured neonatal intestine by stimulating EGC-regulated restitution and closure of associated tight junctions respectively. The proposed experiments will use novel physiologic, cellular, and immunolabeling approaches to define development and repair of porcine mucosa under the influence of two bioactive food components. We believe the proposed studies will lead to an understanding of the mechanistic connections between bioactive nutrients and gut health.

Date: 12/10/19 - 11/30/22
Amount: $152,000.00
Funding Agencies: National Institutes of Health (NIH)

Until recently, tumor evolution was thought to follow a model in which tumor development results from the stepwise accumulation of mutations conferring cancer cells evolutionary fitness advantages required for unregulated growth and metastasis. Recent groundbreaking work demonstrates that, in fact, it is mutations occurring very early during (or even preceding) neoplastic transformation that dictate tumor evolution, and hence some tumors are “born to be bad”. These novel findings further suggest that the potential of a tumor to become malignant is under the influence of (epi)genetic/signaling deregulation whose identification may allow for the distinction between malignant and benign lesions. However, the (epi)genetic/signaling alterations driving susceptibility to neoplastic transformation are poorly understood. Compelling work has demonstrated in several organs, including the intestine, that the cancer cell of origin corresponds to a resident multipotent stem cell that has been (epi)genetically altered. Therefore, identifying (epi)genetic/signaling alterations driving neoplastic transformation in resident intestinal stem cells (ISC) offers the possibility to define specific markers and pathways that may be of interest to allow for early detection of tumor initiation and for new targeted therapies against tumor formation.

Date: 06/01/21 - 5/31/22
Amount: $9,000.00
Funding Agencies: Comparative Gastroenterology Society

Our project last summer focused on neurotransmitters reported in the literature to be present in the gallbladder. Such an approach is confined to what is known. With the objective to more comprehensively understand changes occurring in the intrinsic nervous system of gallbladder mucoceles, in Specific Aim 1 we will perform transcription profiling to identify, quantify, and compare the neurotransmitter content of ganglia from healthy and mucocele gallbladders. In effort to identify pharmacological agents with ability to restore normal gallbladder function, for Specific Aim 2, we will examine the effect of selected neurotransmitters on gallbladder epithelial secretion and absorption ex vivo using Ussing chambers. Our hypothesis is that deficiencies in intrinsic nervous system function can be targeted to help restore normal gallbladder function.

Date: 06/01/21 - 10/01/21
Amount: $5,000.00
Funding Agencies: Triangle Community Foundation

Gallbladder mucocele formation is one of the most common and deadly biliary diseases seen in dogs. The disease is characterized by relentless abnormal mucus secretion by the gallbladder epithelium that may eventually lead to rupture of the gallbladder or obstruction of bile flow. The pathogenesis of gallbladder mucocele formation is poorly understood and treatment options are limited. Surgical removal of the gallbladder can be curative but has a median perioperative mortality of 22%. Evidence supporting the ability of medical management to reverse mucocele formation is limited. The long-range goal of this research is to identify pharmacological treatments capable of preventing or reversing gallbladder mucocele formation in dogs.

Date: 07/15/19 - 1/14/21
Amount: $149,868.00
Funding Agencies: NC Biotechnology Center

The College of Veterinary Medicine at North Carolina State University (NCSU) is requesting funds to acquire an X-RAD 320XL X-Ray irradiator from Precision X-Ray Inc. for cell and small animal research. Using an x-ray tube with a homogenic beam designed for clinical orthovoltage radiation and powered by a 320 kV high frequency ultra-stable x-ray generator, the X-RAD 320XL is capable of precise, repeatable irradiations, and features a chamber able to accommodate specimens as large as mini-pigs. Although irradiation studies are fundamental to the research of a considerable number of investigators at NCSU, there is currently no equipment on campus that offers easy and affordable access to radiation for either cells or small animals. The acquisition of the X-RAD 320XL will hence meet a significant demand from many NSCU investigators whose research spans a broad variety of fields including regenerative medicine, neurobiology, immunology/cancerology, material science and bioengineering, and who represent all departments of the Colleges of Veterinary Medicine and Engineering, as well as faculty colleagues from the joint UNC/NCSU Department of Biomedical Engineering. In the same vein, implementing easy and affordable access to a safe and easy-to-use irradiator on our campus will authorize and stimulate the development of a broad variety of innovative research projects that have been hampered until now. While a significant percentage of the users are already federally funded investigators (NIH, NSF, Army Research Office, USDA), the acquisition of the X-RAD320XL will undoubtedly increase competitiveness for additional federal funding. The high level of qualification of the persons involved, the space availability, the simplicity and safety of use of the X-RAD 320XL, and the strong support from our institution further guarantee the success of the X-RAD 320XL implementation, which will undoubtedly have positive and measureable repercussions for the development of innovative research at NCSU.

Date: 01/01/18 - 12/31/20
Amount: $129,728.00
Funding Agencies: Lineberger Cancer Center

Colorectal cancer is the third deadliest form of cancer. Research over the last decade has demonstrated that only rare cells within the tumor are capable of forming new tumors. These cells have been called cancer stem cells and possess increased potential of chemoresistance, invasion and metastasis. Therefore they are considered responsible for tumor initiation, metastasis and recurrence, and represent highly valuable targets in the development of novel therapies. Relatively recent work has further shown that cancer stem cells are nurtured by their neighboring cells, corresponding to resident and recruited cells that have been hijacked by the tumor to sustain its growth and dissemination. Blocking the remodeling of these neighboring cells or inhibiting their nurturing effects on cancer stem cells represents a very promising approach to fight colorectal cancer. Among all the cell types surrounding cancer stem cells, one in particular has never been studied: the enteric glial cells. These glial cells belong to the nervous system of the digestive tract and form a dense network spreading throughout the entire colonic wall. Based on preliminary studies, this project aims to demonstrate that the remodeling of the glial network induced by the tumor occurs early during colorectal cancer development and nurtures cancer stem cells to promote tumor progression. A comprehensive understanding of the structural and molecular changes induced by the tumor in glial cells as well as of the molecules involved in the nurturing effects of glia on cancer stem cells is likely to lead to novel strategies to treat colorectal cancer.


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