2000 — 2001 |
Caron, Kathleen M |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Cardiovascular Effects of the Adrenomedullin Gene @ University of North Carolina Chapel Hill
The objective of this proposal is to identify the physiological functions of a newly identified vasoactive peptide, Adrenomedullin (Adm). Preliminary studies have suggested a variety of functions for Adm. Most acclaimed is Adm's potential role in blood pressure regulation since it has been found at markedly elevated plasma levels in patients with multiple forms of hypertension. Other studies have implicated Adm in such physiological processes as natriuresis, regulation of aldosterone, ACTH and renin secretion, thirst, embryonic implantation, and cellular proliferation. To examine the function of Adm within an intact physiological milieu, a series of mice will be generated that contain between 0-4 copies of the Adm gene by using the methods of homologous recombination in embryonic stem cells and the mechanisms of gene disruption and gene duplication. The specific aims of this proposal are to: 1) determine the essential biological functions of the Adm gene within an intact physiological milieu by characterizing a knockout mouse model and 2) determine the effects of varying Adm gene expression on blood pressure and related cardiovascular parameters by characterizing a "gene titration" of Adm. Elucidation of the physiological functions of Adm will enhance our general understanding of this new peptide. Moreover, determining the role of Adm in blood pressure regulation will lead to a better understanding of blood pressure homeostasis and may lead to new genetic and pharmacological strategies for the prevention or therapy of hypertension.
|
1 |
2004 — 2006 |
Caron, Kathleen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Phenotype of Genetically Reduced Adm During Pregnancy @ University of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): The physiological and genetic mechanisms responsible for normal placentation and how their perturbation impairs placental blood flow to cause fetal growth restriction (FGR) remain largely unknown. Adrenomedullin (Adm) is a peptide vasodilator that has significant roles during pregnancy. A genetically deficient Adm mouse line is presented as a genetically-induced model of FGR and phenotyping of this model will elucidate the role of Adm in pregnancy and fetal growth. The Iong term objectives of this grant, to reveal the role of Adm in reproduction and to identify genetic and physiological factors that contribute to mechanisms of FGR will be achieved in three aims. Specific Aim I will test the hypothesis that local concentrations of Adm at the maternal-fetal interface are essential for normal placentation and fetal .qrowth. To distinguish between the maternal and fetal contribution of Adm, a novel approach of .qenetically predetermined blastocyst transfer will be used. Pregnancies will be monitored for physiological and pathological indications of preeclampsia and placentas will be analyzed by 3-Dimensional placental casts, histology, ultrasound Doppler and the molecular phenotyping approach described in Specific Aim 2. Specific Aim 2 will develop and validate a novel method for characterizinq placental defects by quantitaion of surrogate gene expression markers to determine if there are common placental pathways that are disrupted in association with FGR. Validation and application of this high-throughput phenotyping screen will be done in collaboration with the N/H-funded Mouse Mutagenesis Center for Deve/opmental Defects at Bay or Col/ege of Medicine. Specific Aim 3 will combine the novel methods of Aims 1 & 2 to ask how maternal chronic diseases, such as hypertension and preeclampsia, exacerbate FGR. Four hypertensive mouse lines, including a genetically-clamped renin transgenic line, a genetically-deficient NPRA line, a genetically-deficient eNOS line and a spontaneously preeclamptic BPH/5 line will be used. Quantitative and comparative evaluation of the phenotypes will identify common genetic mechanisms that underlie the association between maternal hypertension and FGR. Each of the Specific Aims addresses gaps in our current knowledge of the role of Adm in reproduction and the mechanisms underlying FGR. Thus, results from these studies will advance basic science, contribute to better human reproductive health and potentially identify therapeutic interventions that would favorably alter the course of fetal growth in humans.
|
1 |
2007 — 2008 |
Caron, Kathleen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Phenotype of Genetically Reduced Adrenomedullin During Pregnancy @ University of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): The physiological and genetic mechanisms responsible for normal placentation and how their perturbation impairs placental blood flow to cause fetal growth restriction (FGR) remain largely unknown. Adrenomedullin (Adm) is a peptide vasodilator that has significant roles during pregnancy. A genetically deficient Adm mouse line is presented as a genetically-induced model of FGR and phenotyping of this model will elucidate the role of Adm in pregnancy and fetal growth. The Iong term objectives of this grant, to reveal the role of Adm in reproduction and to identify genetic and physiological factors that contribute to mechanisms of FGR will be achieved in three aims. Specific Aim I will test the hypothesis that local concentrations of Adm at the maternal-fetal interface are essential for normal placentation and fetal .qrowth. To distinguish between the maternal and fetal contribution of Adm, a novel approach of .qenetically predetermined blastocyst transfer will be used. Pregnancies will be monitored for physiological and pathological indications of preeclampsia and placentas will be analyzed by 3-Dimensional placental casts, histology, ultrasound Doppler and the molecular phenotyping approach described in Specific Aim 2. Specific Aim 2 will develop and validate a novel method for characterizinq placental defects by quantitaion of surrogate gene expression markers to determine if there are common placental pathways that are disrupted in association with FGR. Validation and application of this high-throughput phenotyping screen will be done in collaboration with the N/H-funded Mouse Mutagenesis Center for Deve/opmental Defects at Bay or Col/ege of Medicine. Specific Aim 3 will combine the novel methods of Aims 1 & 2 to ask how maternal chronic diseases, such as hypertension and preeclampsia, exacerbate FGR. Four hypertensive mouse lines, including a genetically-clamped renin transgenic line, a genetically-deficient NPRA line, a genetically-deficient eNOS line and a spontaneously preeclamptic BPH/5 line will be used. Quantitative and comparative evaluation of the phenotypes will identify common genetic mechanisms that underlie the association between maternal hypertension and FGR. Each of the Specific Aims addresses gaps in our current knowledge of the role of Adm in reproduction and the mechanisms underlying FGR. Thus, results from these studies will advance basic science, contribute to better human reproductive health and potentially identify therapeutic interventions that would favorably alter the course of fetal growth in humans.
|
1 |
2008 — 2011 |
Caron, Kathleen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Adrenomedullin Signaling in Vascular Development @ University of North Carolina Chapel Hill
[unreadable] DESCRIPTION (provided by applicant): The angiogenic peptide vasodilator adrenomedullin (AM) signals through a G-protein coupled receptor (GPCR) called calcitonin receptor-like receptor (CLR) when the receptor is bound to a novel class of proteins called receptor activity modifying proteins (RAMPs). Using genetically engineered mouse models lacking each of the components of AM signaling, we have consistently identified a rare type of embryonic lethality that is characterized by generalized edema caused by defects in lymphangiogenesis. We hypothesize that AM signaling in endothelial cells is an essential mediator of lymphangiogenesis during embryonic development. Our long-term objective, to define the function of AM signaling during lymphatic vascular development can be met in the following aims: Specific Aim 1 is geared toward determining the cellular origin of the lymphatic vascular defects and the dosage of AM signaling required for normal lymphangiogenesis. We will generate and characterize novel genetic mouse models to elucidate i) if AM signaling in endothelial cells is necessary for normal lymphangiogenesis ii) if AM signaling in endothelial cells is sufficient to support normal lymphangiogenesis and iii) the minimum dosage of AM required for normal lymphangiogenesis. Specific Aim 2 will test the hypothesis that AM is a potent modulator of lymphatic endothelial cell proliferation and permeability due to preferential expression of its receptors in lymphatic versus blood endothelial cells. Results from this aim will distinguish genotypic and phenotypic differences between lymphatic and blood vascular cells and will provide a mechanistic basis for the underlying cause of hydrops in the null mouse models. In Specific Aim 3, we plan to identify genetic pathways that interact with the AM Signaling System to modulate its functions either in healthy or edematous lymphatic vasculature. The functional significance of positively identified pathways will be confirmed through an embryoid body culture system, in vivo corneal neovascularization assays and tail microlymphography. Results from this aim will define the functional consequences of altered AM activity in the lymphatic vasculature and will elucidate how this pathway interacts with other pathways to mediate lymphangiogenesis. By completing these aims we hope to provide novel insights into the processes that govern lymphangiogenesis during development and thus identify a new class of protein targets which can modulate the lymphatic vasculature for the treatment of conditions such as lymphedema or the inhibition of tumor metastasis. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE We have demonstrated that genes required for mediating the signal of a potent angiogenic peptide, adrenomedullin, are required for lymphangiogenesis during embryonic development. We plan to elucidate the functions of AM signaling in the lymphatic vasculature. In doing so, we hope to provide novel insights into the processes that govern lymphangiogenesis during development and thus identify a new class of protein targets which can modulate the lymphatic vasculature for the treatment of conditions such as lymphedema or the inhibition of tumor metastasis. [unreadable] [unreadable] [unreadable]
|
1 |
2009 — 2019 |
Caron, Kathleen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Adrenomedullin Signaling At the Maternal-Fetal Interface @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): The multifunctional peptide vasodilator adrenomedullin (AM) typically signals through a G-protein coupled receptor (GPCR) called calcitonin receptor-like receptor (Calcrl) when the receptor is bound to a novel class of proteins called receptor activity modifying proteins (RAMPs). Using genetically engineered mouse models lacking each of the components of AM signaling, we have found that both maternal and fetal sources of AM signaling are important for orchestrating appropriate implantation and placentation that are required for normal fetal growth. We have shown that maternal AM is involved in the endocrine preparation of the uterus for receptivity to the blastocyst and that a modest 50% reduction in maternal AM levels is sufficient to induce profound reproductive defects associated with poor implantation and placentation. While complete absence of AM and its canonical receptors leads to embryonic lethality due to defects in lymphangiogenesis, we have discovered that fetal AM is also required for the normal branching angiogenesis of the labyrinth layer at mid-gestation. However, we have yet to fully understand the cellular mechanisms through which AM signaling mediates these reproductive effects at the maternal-fetal interface. Surprisingly, not all of the phenotypes in the AM genetic model are recapitulated in the CLR and RAMP2 models, which suggests that the functions of AM may be imparted through receptor-independent pathways or through as yet under-appreciated receptor signaling paradigms. In this regard, AM peptide binds to and potentiates the activity of Complement Factor H, a negative inhibitor of the alternative complement pathway that is important for normal implantation. In addition, AM peptide has also been shown to activate a chemokine receptor, CXCR7. Therefore, studies in this proposal are aimed at elucidating the potential roles of AM as a regulator of the innate immune response at the maternal-fetal interface through canonical, non-canonical or receptor- independent mechanisms. Our goals will be met through the following aims: Specific Aim 1 is geared toward determining the spatial and temporal expression pattern of AM, Complement Factor H and CXCR7 during the pre-receptive, receptive and refractory uterine phases. Using a novel genetic mouse model and genetically pre-determined blastocyst transfer experiments, we will determine whether fetal and/or maternal sources of AM can influence the expression of these signaling molecules at the maternal-fetal interface. In Specific Aim 2 we will address whether changes in the genetic dosage of AM signaling can affect the alternative complement pathway at the maternal-fetal interface. In Specific Aim 3 we will test whether AM signaling through CXCR7 represents a major mechanism for the appropriate remodeling of maternal spiral arteries during implantation. By completing these aims we hope to provide novel insights into the processes that govern the delicate dialogue between mother and fetus and provide a molecular link between trophoblast-derived factors that influence the maternal immune response during implantation. PUBLIC HEALTH RELEVANCE: We have discovered that both maternal and fetal sources of AM signaling are important for orchestrating appropriate implantation and placentation. We hypothesize that AM, acting through non-canonical pathways, represents an important fetal-derived signal for modulating the maternal innate immune response. If we are correct, then we will provide novel insights into the processes that govern the delicate dialogue between mother and fetus and provide a molecular link between trophoblast- derived factors that influence the maternal immune response during implantation.
|
0.988 |
2013 — 2016 |
Caron, Kathleen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Causes and Consequences of Digestive Tract Lymphangiectasia @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): In the past dozen years, an expanded repertoire of genes and molecular pathways involved in the development of the lymphatic vascular system has been elucidated. However, considering the essential role of lymphatic vessels in intestinal lipid absorption and the increased prevalence of inflammatory diseases of the intestine, it is rather remarkable that there are currently more questions than answers regarding whether and/or how lymphatic vessels contribute to (or may be causative of) pathophysiological diseases in adults-as recently highlighted in the NIDDK-sponsored PAR-12- 259. We propose to directly address many of these questions by building upon our exciting discoveries on the essential roles of signaling in lymphatics. Our laboratory was the first to provide genetic in vivo evidence for the importance of the AM signaling pathway in embryonic development since AM-/-, CLR-/- and RAMP2-/- mice die at midgestation with a conserved phenotype that consists of profound interstitial edema caused by arrested lymphangiogenesis. In addition, our most recent studies have used an inducible knockout allele to show that loss of CLR in adult animals fully recapitulates the clinical sequelae related to lymphangiectasia, including dilated lymphatics, reduced intestinal lipid absorption, protein losing enteropathy and limb edema. Studies proposed in this grant application will build upon these exciting findings and strive to elucidate the physiological and molecular processes that lymphatics play in i) intestinal disease initiation and progression, ii) normal intestinal lipid absorption under a variety of different challenge conditions and iii) the initiation and progression of mucosal injury, inflammation and repair. By completing these aims we hope to provide novel insights into the role of lymphatic vessels and AM signaling in the intestinal tract. The elucidation of these molecular pathways may ultimately form the basis of GPCR- targeted approaches for the therapeutic modulation of intestinal lymphatic vessels, particularly during lymphangiectasia and disease conditions associated with digestive tract inflammation.
|
0.988 |
2016 — 2019 |
Caron, Kathleen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cardiac Lymphatics in Heart Failure @ Univ of North Carolina Chapel Hill
? DESCRIPTION (provided by applicant): Lymphatic vessels serve an essential function in maintaining interstitial fluid balance throughout the body. They also serve as a conduit for the trafficking and maturation of immune cells. Functional disruption of lymphatic vessels by either surgery, radiation/chemotherapy or organ damage results in pathological lymphedema and subsequent interstitial fibrous deposition and inflammation. The heart contains a dense network of lymphatic vessels that exhibit coordinated flow with each contraction of the myocardium. However, whether lymphatic dysfunction contributes to the pathophysiological progression of heart injury following myocardial ischemia remains unknown. Furthermore, we lack a full understanding of the consequences of myocardial edema on heart function following ischemic heart disease. Therefore the overall goal of this research proposal is to develop sophisticated surgical and genetic mouse model tools to address the function and modulation of cardiac lymphatic vessels in heart disease. Based on our expertise in lymphatic vessel biology and our interest in the cardioprotective functions of adrenomedullin peptide, we feel that we are uniquely well- positioned to address the effects of either increased cardiac lymphatics or lymphatic insufficiency on the resolution or exacerbation of myocardial edema, respectively. Results from our studies will provide conceptually novel insights into the largely unexplored role of cardiac lymphatic vessels in myocardial edema.
|
0.988 |
2019 — 2021 |
Caron, Kathleen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gpcr-Mediated Pathways For Regulation of Intestinal Lymphatic Function @ Univ of North Carolina Chapel Hill
Abstract G protein-coupled receptors (GPCRs) represent the largest class of pharmacological targets in modern medicine, accounting for over 60% of all prescriptions worldwide. Yet, of the ~345 non- olfactory GPCRs, many remain either orphan (with no known ligand) or uncharacterized (with no clear physiological function). Therefore, discovering the spatiotemporal regulation and function of GPCRs within pharmaceutically- and physiologically-understudied systems is of great clinical importance. Considering the essential role of lymphatic vessels in intestinal lipid absorption and the increased prevalence of inflammatory and metabolic diseases of the intestine, it is rather remarkable that there are currently more questions than answers regarding whether and/or how lymphatic vessels contribute to normal digestive function and/or diseases in adults. Therefore, studies proposed in this grant have been purposefully designed to address numerous key questions raised by the recent NIH/NIDDK-sponsored RFA-DK-17-016 entitled: Lymphatics in Health and Disease in the Digestive System. Using state-of-the-art biochemical, proteomic, genomic and animal model approaches, we propose to build on our current expertise on the CLR-AM signaling axis within the lymphatic vascular system. Ultimately, we hope our studies will expand the repertoire of GPCR pathways that play important functions in the regulation of the neurolymphocrine unit within the GI tract, and potentially uncover unique and pharmacologically-tractable pathways for the improvement of digestive health.
|
0.988 |
2020 |
Caron, Kathleen M |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
2020 Lymphatics Gordon Research Conference and Gordon Research Seminar @ Gordon Research Conferences
Abstract The 2020 Gordon Research Conference on Lymphatics will bring together leading international scientists and clinicians working across all aspects of lymphatic vessel biology to discuss the latest advances in this exciting and dynamic field. The meeting will feature cutting edge expertise in disciplines including developmental biology, genetics, physiology, immunology, metabolism, mechanotransduction and human disease. The lymphatic vasculature has garnered immense attention over the last decade, fueled by advances in our ability to recognize and manipulate lymphatic vessels, together with discoveries that have illuminated key roles for the lymphatic vasculature in human health and disease. Sometimes referred to as the ?third circulatory system?, the principal function of the lymphatic system in regulating interstitial fluid dynamics is of direct relevance to the missions of NHLBI. The NHLBI has historically provided support to this field with regard to this particular conference, as well as Workshops and focused Program Announcements. This meeting, which includes many speakers currently funded by the NHLBI, will serve as a forum to communicate the latest research advances in this field as well as providing the opportunity to build collaborative partnerships between scientists, clinicians, disciplines, industry and philanthropy.
|
0.904 |
2020 — 2021 |
Caron, Kathleen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cardiac Lymphatics in Development and Repair @ Univ of North Carolina Chapel Hill
Project Abstract Lymphatic vessels serve an essential function in maintaining interstitial fluid balance throughout the body. Functional disruption of lymphatic vessels by either surgery, radiation/chemotherapy or organ damage results in pathological lymphedema and subsequent interstitial fibrous deposition and inflammation. The heart contains a dense network of lymphatic vessels that exhibit coordinated flow with each contraction of the myocardium. Recent studies, including our own, have revealed a critical role for cardiac lymphatics in cardiac repair and maintenance of cardiac function following acute myocardial edema. Several groundbreaking studies have furthermore shown that cardiac lymphatics arise from at least 4 different progenitor cell populations, thereby illustrating their distinct and pleiotropic regulation during development and conditions of remodeling and repair. We have also discovered a significant increase in the number of cardiac lymphatics of female mice, compared to age-matched male mice, which could be the basis underlying some forms of cardioprotection in women. Therefore, the overall goal of this research proposal is to develop sophisticated cell based systems and genetic mouse model tools to address the function and modulation of cardiac lymphatic vessels in males and females and during different stages of development and repair. Based on our expertise in lymphatic vessel biology and our interest in the cardioprotective functions of adrenomedullin peptide, we feel that we are uniquely well-positioned to address several intriguing hypotheses. Results from our studies will provide conceptually novel insights into the largely unexplored role of cardiac lymphatic vessels in heart development, injury and sex-dependent cardioprotection.
|
0.988 |
2020 — 2021 |
Caron, Kathleen M Conlon, Frank Leo (co-PI) [⬀] |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training Program in Cellular Systems and Integrative Physiology @ Univ of North Carolina Chapel Hill
ABSTRACT The Training Program in Cellular Systems and Integrative Physiology (CSIP) at UNC-Chapel Hill is a multidisciplinary predoctoral training program that uses a systems approach to provide comprehensive, biomedical graduate education to our trainees. The CSIP program is designed around evidence-based training activities, including didactic coursework, seminar courses focusing on scientific communication and grant-writing, career building activities, and novel doctoral research. Our rationale is that by combining these training approaches, the UNC CSIP Training Program will produce a diverse pool of well-trained scientists and leaders with the skills necessary to transition into successful careers in the biomedical research workforce. The multidisciplinary and interdepartmental CSIP Training Program draws its mentoring faculty and leadership members from 8 basic science departments (Biochemistry and Biophysics, Biology, Biomedical Engineering, Cell Biology and Physiology, Genetics, Microbiology and Immunology, Pathology, and Pharmacology) and 7 clinical departments (Medicine, Neurology, Nutrition, Oral and Craniofacial Health Sciences, Pediatrics, Psychiatry, and Surgery) that span the UNC School of Medicine, the College of Arts and Sciences, and the School of Public Health. The CSIP Training Program will transcend these individual departments to provide hands-on training and mentorship from our collaborative faculty and extracurricular, structured training opportunities across the CSIP departments. Our distinguished faculty emphasize rigor, transparency, integrity, and creative scientific reasoning that provide a broad, integrated biological foundation centered on organ systems and human diseases and have the vast resources of UNC at their disposal. By going beyond the minimum requirements of the Ph.D. granting departments and curriculums, the CSIP Training Program will serve as a model for graduate student training and education. In support of the CSIP Training Program, we request 5 years of funding to train predoctoral students for 2 years in the cellular and physiological processes of higher organisms across various scales (from molecular to whole-organism) and provide meaningful career development activities designed to prepare a diverse student population for a variety of biomedical career paths. The University of North Carolina is a national leader in developed programs to support ethnic, cultural, and physical diversity and the CSIP Training Program will strive to continue and build upon this strong tradition. .
|
0.988 |
2021 |
Caron, Kathleen M |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Illuminating Orphan Gpcrs in Lymphatics @ Univ of North Carolina Chapel Hill
ABSTRACT Since more than 40% of all clinically-available drugs target G-protein coupled receptors (GPCRs), there is great interest in learning more about this family of proteins in order to discover new therapeutic targets. When considering the different classes of proteins encoded by the human genome that are predicted to be pharmacologically-tractable, a remarkable one quarter represent GPCRs. And yet, of the ~345 non-odorant GPCRs a large proportion remain orphan?with no known ligand?or have uncharacterized physiological functions. Since we have a dearth of pharmacological targets for lymphatic vessels, it stands to reason that focused efforts to explore and characterize the lymphatic ?GPCRome? is a worthwhile endeavor. We have identified 3 orphan GPCRs that are IDG-eligible target proteins in the Illuminating the Druggable Genome (IDG) Project. We propose to develop and use in vitro and animal-based systems to further characterize the expression and activation of these GPCRs in the lymphatic vasculature. Our results will further the overall goals of the IDG Consortium and reveal novel physiological pathways and potential therapeutic targets for the modulation of lymphatics, which remains an understudied research area with unmet clinical needs.
|
0.988 |