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Principal Investigator: Bhama Ramkhelawon
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2019
Award: $240,854
Funding agency: National Heart Lung and Blood Institute
Dr. Bhama Ramkhelawon nourishes 2 career goals during this award. An immediate goal to gain
knowledge into the expression of the neuronal guidance cue, Netrin-1 in macrophage-elicited inflammation in
Abdominal Aortic Aneurysms (AAAs) and a long-term career goal to become an independent investigator
capable of leading
research and ascribe a possible role Netrin-1 as a novel target for development of therapies
to curb the burden of AAA. AAA is characterized by a focal dilation of the aortic diameter >30 mm located in
the infrarenal section of the aorta. Roughly 25,000 AAA repairs are performed each year, and despite progress
in primary preventive measures, AAA still accounts for > 13,000 deaths annually in the United States. Previous
histological studies have revealed that transmural inflammation is manifested by the presence of
monocytes/macrophages. This inflammation is associated with the proteolytic destruction of the aortic wall
through the degradation of elastin and collagen by matrix metalloproteinases (MMPs). Numerous studies have
profoundly explored the mechanisms related to the proteolitic disruption of the blood vessel. To better
appreciate preventive therapeutic strategies, it is crucial to understand the broad spectrum of the
physiopathology. Since Mø have important roles in both the induction and resolution of inflammation, I
hypothesize that in addition to signals directing their recruitment to the focal site of aortic dilation, other cues
are expressed to orient the advanced avenues related to the laminal destructive capacity of these cells. We
have recently demonstrated a critical role for the neuronal guidance cue, Netrin-1 in promoting atherosclerosis
by blocking their chemotaxis to exit signals such as CCL-19. Interestingly, my preliminary data show that the
signals (IL-6 and TNfa) that direct Mø recruitment can also induce the expression of retention cues such as
Netrin-1 in both mice and clinical human AAA specimens. We propose another innovative role for Netrin-1 in
orchestrating AAA-induced inflammation in a non-lipidemic environment. In this grant, we will use novel mouse
models of tissue-specific or conditional deletion of Netrin-1 to determine how this guidance cue alters the
dynamic regulation of Mø into AAA sites, and direct their polarization.
During the mentored research phase (K99), I will complete my ongoing research projects under Dr.
Moore’s supervision at New York University Langone Medical Center. I will gain expertise in important aspects
of Mø elicited inflammation in AAA in her laboratory. I will take the opportunity of all the facilities available at
the research center to perform key experiments required to study AAA and hence specialize myself in this field.
Dr. Moore will serve as Primary Mentor and oversee all aspects of my transition to become an
Independent Researcher. Together we have elaborated a career development plan, which encompasses
guidance in project progress, manuscript and grant writing, animal breeding, congress attendance and to
perform training in the responsible conduct of research. In addition, a team of four Co-Mentors will provide me
with complementary research guidance and help which will greatly enhance and diversify my research skill set.
Together, the team of Mentors has pledged to guide me to extend my research interests and approaches, and
to ensure a successful transition to an independent researcher.
During the independent phase (R00) of this award, I will test the therapeutic avenues of silencing
Netrin-1 by using nanoparticles encapsulating siRNA in the AAA mouse model. We expect to successfully
dampen Mø inflammation associated with vessel wall destruction by targeting Netrin-1 in vivo. These
experiments will provide key insights into promising surgery alternatives and will head toward translationally
applied future drug development to treat AAA.
Terms: <(TNF)-α><Abdomen><Abdominal><Abdominal Aortic Aneurysm><Active Oxygen><Address><Affect><Animal Model><Animal Models and Related Studies><Aorta><Aortic Diseases><Aortic Rupture><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Award><B cell differentiation factor><B cell growth factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor Gene><B-Cell Differentiation Factor-1><B-Cell Differentiation Factor-2><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor 2 Gene><B-Cell Stimulatory Factor-1><B-Cell Stimulatory Factor-2><BCDF><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF-2><BSF-2 Gene><BSF1><BSF2><BSF2 Gene><Beta-2 Gene Interferon><Binetrakin><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Vessels><Blood monocyte><Body Tissues><CCL2><CCL2 gene><CSIF><CSIF-10><Cachectin><Caliber><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Chemoattractants><Chemokine, CC Motif, Ligand 2><Chemotactic Factors><Chemotaxins><Chemotaxis><Clinical><Collagen><Conflict><Conflict (Psychology)><Congresses><Country><Cues><Cytokine Synthesis Inhibitory Factor><Data><Death><Deterioration><Development><Development Plans><Diameter><Disease><Disease Progression><Disorder><Drug Therapy><Dysfunction><Elastin><Elderly man><Emigrations><Encapsulated><Ensure><Environment><Equilibrium><Foam Cells><Fostering><Functional disorder><Future><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Genes><Goals><Grant><HPGF><HSF Gene><Head><Hematopoietic><Hepatocyte Stimulatory Factor Gene><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><Hybridoma Growth Factor Gene><IFN-beta 2><IFNB2><IFNB2 Gene><IL-10><IL-4><IL-6><IL-6 Gene><IL10><IL10A><IL4 Protein><IL6><IL6 Protein><IL6 gene><Immune><Immunes><Incidence><Individual><Infiltration><Inflammation><Inflammatory><Interleukin 10 Precursor><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin-10><Interleukin-4><Interleukin-4 Precursor><Interleukin-6><Interleukin-6 Gene><Intracellular Communication and Signaling><Investigators><Knowledge><Label><Laboratories><Latex Bead><Lead><Leanness><Life><Lipids><Lymphocyte><Lymphocyte Stimulatory Factor 1><Lymphocytic><MCAF><MCGF-2><MCP-1><MCP1><MGI-2><MMPs><Macrophage-Derived TNF><Manuscripts><Marrow Mast Cell><Marrow Neutrophil><Marrow monocyte><Mast Cell Growth Factor-2><Matrix Metalloproteinases><Medial><Medical center><Mentors><Mice><Mice Mammals><Modern Man><Monitor><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Monocyte-Derived TNF><Mouse Homolog of NETRIN 1><Murine><Mus><Myeloid Differentiation-Inducing Protein><NETRIN 1-Like><NTN1><NTN1 gene><NTN1 gene product><NTN1L><Neutrophilic Granulocyte><Neutrophilic Leukocyte><New York><Operative Procedures><Operative Surgical Procedures><Oxygen Radicals><Pathology><Patients><Pb element><Pharmacotherapy><Phase><Physiopathology><Plasmacytoma Growth Factor><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Preventative measure><Preventive><Preventive measure><Pro-Oxidants><R-Series Research Projects><R01 Mechanism><R01 Program><Reaction><Reactive Oxygen Species><Receptor Protein><Regulation><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Research Specimen><Researchers><Resolution><Role><Rupture><SCYA2><Severity of illness><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Inducible Cytokine A2><Small Interfering RNA><Specimen><Stents><Structure><Supervision><Surgical><Surgical Interventions><Surgical Procedure><T-Cell Growth Factor 2><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Tamoxifen><Techniques><Testing><Therapeutic><Thinness><Tissue Basophils><Tissue Model><Tissues><Training><Transcript Expression Analyses><Transcript Expression Analysis><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><United States><Universities><Up-Regulation><Upregulation><Writing><animal breeding><aorta disease><aorta disorder><aortic disorder><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><balance><balance function><base><biocompatibility><biological signal transduction><biomaterial compatibility><career><career development><complement chemotactic factor><cytokine><develop therapy><developmental><disease severity><drug development><drug treatment><experiment><experimental research><experimental study><gene expression analysis><gene expression assay><heavy metal Pb><heavy metal lead><hemopoietic><histologic studies><histological studies><in vivo><innovate><innovation><innovative><insight><interest><interferon beta 2><intervention development><laser capture microdissection><lipid nanoparticle><lymph cell><macrophage><mast cell><mastocyte><meeting reports><migration><model of animal><model organism><monocyte><mouse model><murine model><nano materials><nano particle><nano-sized particle><nano-string><nanomaterials><nanoparticle><nanosized particle><nanostring><netrin-1><neuronal guidance><neutrophil><novel><pathophysiology><prevent><preventing><receptor><recruit><repair><repaired><response><responsible research conduct><siRNA><skills><social role><surgery><therapeutic evaluation><therapeutic testing><therapy development><tissue repair><trafficking><transcriptional profiling><treatment development><vascular><vulnerable plaque>