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Principal Investigator: Gregory Westcott
Organization: BETH ISRAEL DEACONESS MEDICAL CENTER
Fiscal Year: 2024
Award: $164,484
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
Adipose tissue homeostasis and expansion requires the coordination of multiple cell types to accommodate
increases in tissue volume and metabolic requirements. An important component of adipose tissue regulation is
the lymphatic vascular system, which is responsible for the removal of extracellular fluid and for immune cell
trafficking from the tissue to lymph nodes. In obesity, the relationship between fat and lymphatics becomes
dysregulated, resulting in lymphatic vessel dysfunction, including decreased vessel formation, increased
permeability, and diminished contractility. Conversely, in conditions of impaired lymphatic function, such as after
lymph node resection, adipose tissue is dysregulated and experiences accelerated expansion in the affected
area.
Given the increasing prevalence of obesity and its complications, as well as the burden of lymphedema in millions
of post-surgical patients, the mechanisms which regulate the relationship between adipose tissue and lymphatics
are of significant interest. Broadly, this proposal will investigate cell-type specific interactions which govern this
relationship. The lab’s single-nucleus RNA sequencing data revealed that lymphatic endothelial cells express
the leptin receptor, indicating a role for leptin—an adipocyte-produced hormone which regulates organismal
energy balance—in lymphatic function. Preliminary studies have demonstrated that leptin augments lymphatic
tube formation and impacts gene expression, and Aim 1 of this proposal describes a plan to further define leptin’s
role in lymphatic function. Aim 2 proposes to study the adipocyte-lymphatic relationship from an alternative
direction by performing single-nucleus RNA sequencing on adipose tissue associated with lymphedema in
human subjects, thereby revealing changes in cellular composition and transcriptional profiles after disruption of
local lymphatics.
This five-year career development program will build on and expand the candidate’s skills and experience in
studying adipocyte biology, animal models of metabolic dysfunction, and single-cell RNA sequencing, while also
employing a number of new techniques to evaluate lymphatic vessel function. By assembling a mentorship team
and collaborators who are well-equipped to facilitate these studies, in addition to supplementary didactic work,
this project will enable the candidate’s transition to an independent career as a physician-scientist in the fields
of adipose tissue biology and metabolism.
Terms: <21+ years old><Abscission><Acceleration><Adipocytes><Adipose Cell><Adipose tissue><Adult><Adult Human><Affect><Animal Model><Animal Models and Related Studies><Appetite><Area><Autoregulation><Biological><Biology><Body Composition><Body Tissues><Body Weight><Body fat><Boston><Breast Cancer Treatment><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Chronic><Clinical><Collaborations><Complex><Data><Deposit><Deposition><Desire for food><Development><Disease><Disorder><Dysfunction><Endocrine Gland Secretion><Evaluation><Excision><Expression Signature><Extirpation><Extracellular Fluid><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><Functional disorder><Future><Gene Expression><Gene Expression Profile><Gene Transcription><Genetic Transcription><Goals><Health><Heat Production><Histologic><Histologically><Histology><Homeostasis><Hormones><HuB219><Human><Hypertrophy><Immune><Immunes><Impairment><Insulin Resistance><Intercellular Fluid><Intermediary Metabolism><Interstitial Fluids><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><LEP-R><LEPR Protein><Leptin><Leptin resistance><Ligands><Lipedema><Lipocytes><Liquid substance><Lymph Node Reticuloendothelial System><Lymph System><Lymph node proper><Lymphangiogeneses><Lymphangiogenesis><Lymphatic><Lymphatic Abnormalities><Lymphatic Diseases><Lymphatic Endothelial Cells><Lymphatic Network><Lymphatic System><Lymphatic System Reticuloendothelial System><Lymphatic anomalies><Lymphatic clearance><Lymphatic defects><Lymphatic function><Lymphatic nodes><Lymphedema><Mature Lipocyte><Mature fat cell><Mediating><Mentors><Mentorship><Metabolic><Metabolic Processes><Metabolic dysfunction><Metabolism><Mice><Mice Mammals><Modern Man><Murine><Mus><Neurotensin><Null Mouse><OB Receptor><OB-R><Ob Gene Product><Ob Protein><Obese Gene Product><Obese Protein><Obesity><Operative Procedures><Operative Surgical Procedures><Paracrine Communication><Paracrine Signaling><Pathology><Patients><Permeability><Physicians><Physiological Homeostasis><Physiology><Physiopathology><Prevalence><Program Development><Proliferating><Publishing><RNA Expression><Receptor Protein><Regulation><Removal><Research Resources><Resolution><Resources><Risk Factors><Role><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Single-Nucleus Sequencing><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><System><Techniques><Therapeutic Hormone><Thermogenesis><Tissue Differentiation><Tissue Expansion><Tissues><Transcription><Tube><Vascular System><Weight Gain><Weight Increase><Work><adipocyte biology><adipose><adiposity><adulthood><biologic><biological signal transduction><body weight gain><body weight increase><career><career development><cell type><corpulence><developmental><energy balance><experience><fluid><gene expression pattern><gene expression signature><human subject><improved><insight><insulin resistant><insulin tolerance><interest><leptin receptor><leptin-binding protein><liquid><lymph channel><lymph edema><lymph flow><lymph gland><lymph nodes><lymph vessel><lymphatic channel><lymphatic disorder><lymphatic dysfunction><lymphatic edema><lymphatic flow><lymphatic impairment><lymphatic malformations><lymphatic vasculature><lymphatic vessel><lymphnodes><model of animal><mouse model><murine model><pathophysiology><programs><receptor><resection><resolutions><sNuc-Seq><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single nucleus RNA-sequencing><single nucleus seq><single-cell RNA sequencing><single-nucleus RNA-seq><skills><snRNA sequencing><snRNA-seq><social role><subcutaneous><subdermal><surgery><trafficking><transcriptional profile><transcriptional signature><uptake><white adipose tissue><wt gain><yellow adipose tissue>