Document text
Principal Investigator: Kui Cui
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $125,658
Funding agency: National Heart Lung and Blood Institute
Abstract
The long-term goal of this proposal is developed to uncover the molecular mechanisms and identify
critical regulators governing lymphatic vascular function in health and disease in hopes of offering
potential new therapeutic targets to combat cardiovascular and metabolic disorders. At the third year
of postdoctoral training, the PI has published his first postdoctoral project and presented his studies in
several prestigious conferences that pave the way for his transition to an independent investigator.
The lymphatic system is responsible for maintaining interstitial fluid homeostasis, immune cell
trafficking and lipid absorption. Lymphatic function participates largely in the pathogenesis of metabolic
and cardiovascular diseases such as obesity and atherosclerosis. How lymphatic dysfunction leads to
abnormal lipid transport and fat deposition, and conversely, how these metabolic diseases impair
lymphatic function are poorly understood but highly medically relevant questions. Embryonic mice
lacking Foxc2, a key transcription factor, prevents the formation and maturation of collecting lymphatic
vessels. Despite the crucial role of Foxc2 in lymphatic development and remodeling, little is known
about the role of Foxc2 in adult physiological and pathological lymphatic function; limitation is largely
due to a lack of appropriate animal models. In this proposed application, the PI recently has generated
novel inducible lymphatic endothelial cell (LEC)-specific Foxc2 gain-of-function and Foxc2 loss-of-
function mice. Utilizing these powerful genetic tools, the PI observed that deficiency of LEC Foxc2 in
adult mice dramatically increased the lymphangiogensis, improves impaired lymphatic drainage and
lipid absorption in metabolic disorders (unpublished data). In the K99 phase, the PI will continue the
current project to determine the molecular mechanism by which Foxc2 regulates adult
lymphangiogenesis and lymphatic function in obese model. While in R00 phase, the PI will investigate
the role of Foxc2 in modulating macrophage cholesterol efflux and reverse cholesterol transport in
atherosclerotic model, as well as how Foxc2 will affect atherogenesis, which is diverging from his
mentor’s work on Epsin, a family of endocytic adaptor proteins. Moreover, other than the unique mouse
models and cutting-edge techniques, the PI will develop a novel LEC-specific nanoparticle delivery
system based on his recent published platform to specifically target LEC Foxc2, thus may halt
inflammation and inhibit atheroma progression. This proposal will be valuable for restoring impaired
lymphatics to treat cardiovascular and metabolic diseases.
Terms: <21+ years old><Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Address><Adult><Adult Human><Affect><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Aorta><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Attenuated><Basal Transcription Factor><Basal transcription factor genes><Blood><Blood Reticuloendothelial System><Blood Vessels><Body Tissues><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cholesterol><Chronic><Clinical><Data><Deposit><Deposition><Development><Disease><Disorder><Embryo><Embryonic><FLT4 Protein><FMS-Related Tyrosine Kinase 4><FOXC2><FOXC2 gene><Family><Fats><Fatty acid glycerol esters><Flt-4><Fluid Balance><Fluid Homeostasis><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Transcription><Goals><Health><High Fat Diet><Human><Hypercholesteremia><Immune><Immune response><Immunes><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Inflammation><Insulin Resistance><Intercellular Fluid><Interstitial Fluids><Intracellular Communication and Signaling><Investigators><Lipid Trafficking><Lipids><Lymph System><Lymphangiogeneses><Lymphangiogenesis><Lymphatic><Lymphatic Endothelial Cells><Lymphatic Endothelium><Lymphatic Network><Lymphatic System><Lymphatic System Reticuloendothelial System><Lymphatic function><Lymphedema><Macrophage><Medical><Mentors><Metabolic><Metabolic Diseases><Metabolic Disorder><Metastasis Suppression><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Tumor Suppression><Murine><Mus><Mφ><Obese Mice><Obesity><Pathogenesis><Pathologic><Peripheral><Phase><Physiologic><Physiological><Play><Postdoc><Postdoctoral Fellow><Process><Publishing><RNA Expression><Research Associate><Research Personnel><Researchers><Resolution><Role><Signal Induction><Signal Transduction><Signal Transduction Systems><Signaling><Stream><System><Techniques><Testing><Therapeutic><Thesaurismosis><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Tumor Suppression><Tyrosine-Protein Kinase Receptor FLT4><VEGFR-3><VEGFR3><Vascular Endothelial Growth Factor Receptor-3><Work><absorption><adapter protein><adiposity><adulthood><atherogenesis><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><attenuate><attenuates><biological signal transduction><cardiovascular disorder><combat><conference><convention><corpulence><developmental><diet-associated obesity><diet-induced obesity><diet-related obesity><epsin><fat metabolism><gain of function><high blood cholesterol><host response><hypercholesterolemia><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><insulin resistant><insulin tolerance><lipid metabolism><lipid transport><loss of function><lymph channel><lymph edema><lymph flow><lymph vessel><lymphatic channel><lymphatic development><lymphatic drainage><lymphatic dysfunction><lymphatic edema><lymphatic flow><lymphatic formation><lymphatic impairment><lymphatic vessel><metabolism disorder><model of animal><mouse model><murine model><nano particle delivery><nano therapy><nanoparticle delivered><nanoparticle delivery><nanotherapy><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ob/ob mouse><obese patients><older adult><older adulthood><patients with obesity><post-doc><post-doctoral><post-doctoral trainee><post-doctoral training><postdoctoral training><prevent><preventing><regenerative><research associates><resolutions><restoration><reverse cholesterol transport><social role><summit><symposia><symposium><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tool><trafficking><transcription factor><vascular><vulnerable plaque>