Control of adipose immune-stromal niche topography in obesity

PROJECT SUMMARY Obesity affects nearly half of the adult US population and is a risk factor for adverse cardiovascular events such as stroke and cardiac arrest, and Type II diabetes. Obesity promotes inflammation of the visceral adipose tissue (VAT), which in turn drives hyperglycemia, insulin resistance, and contributes to cardiovascular inflammation. Therefore, my long-term research goal is understanding the breakdown of tissue homeostatic mechanisms in the VAT, which may help understand and lead to treatments that constrain the development of obesity-associated inflammation. The overall objective of this proposal is to delineate adipose tissue topography using a multimodal approach through spatial sequencing, thick section confocal microscopy and flow cytometry to identify novel signaling or cell populations as therapeutic targets for treatment of obesity-associated inflammation. Profiling stromal and immune cells in the eVAT, I’ve shown their close association and remodeling during high fat diet. Based on these data, my central hypothesis is that obesity alters eVAT tissue topography, thus bringing together signaling partners that drive inflammatory and pro-fibrotic reprogramming responsible for resident lymphoid and body-wide metabolic dysfunction. I propose to study the spatial and temporal relationships among immune and fibroblasts in obesifying eVAT in two aims. In Aim 1, I will topographically delineate fibroblast contributions to obese tissue architecture and in Aim 2, I will assess immune cell contribution and identify unique cellular signatures and interactions in mouse and human adipose using spatial sequencing. Having completed my MD PhD and residency in Clinical Pathology and fellowship in Cellular Therapy and Transfusion Medicine, I am now pursuing research as an R38-funded StARR scholar. I am applying for the K38 StARRTS Award to support my goal of becoming an independent physician-scientist. The exceptional training program at UCSF, especially in the immunology and obesity fields, will support my effort. Key parts of my training program leverage several aspects of this environment, including mentorship by Dr Ari Molofsky, an expert in tissue immune and stromal niches; co-mentorship by Dr Richard Locksley, an expert in Type 2 immunity, and in vivo immunology; co-mentorship by Dr Suneil Koliwad, an expert in obesity-associated inflammation and diabetes; guidance by a multidisciplinary advisory committee and collaborations with Drs Mike Rosenblum and Dean Sheppard, experts in spatial sequencing and fibrosis, respectively; coursework in data science, biostatistics, and research ethics; and professional development activities. Altogether, this career development plan will establish a strong foundation for me to unravel mechanisms of obesity-associated inflammation and for advancing towards an independent research program as a physician-scientist.