Payel Roy, Ph.D.

Can we diagnose early signs of heart disease using blood test-based screening strategy?

FUNDED: JANUARY 2021
FUNDED BY: the generosity of The Rickey Family

Millions of Americans die every year due to stroke or heart attack. The pathological condition that leads to such fatal consequences is called atherosclerosis. It is characterized by a gradual build-up of fatty deposits that narrows or clogs arteries. These deposits disrupt blood flow and reduce oxygen and nutrient supply to major organs such as the heart and the brain. What makes atherosclerosis so insidious is a long asymptomatic phase during which the disease progresses silently. Sometimes the disease is detected at such advanced stages that it is too late to prevent a heart attack or a stroke. My project explores developing a simple yet efficient blood test-based screening strategy that can identify “at-risk” individuals early on so that we can avoid such fatal consequences.

Traditionally, atherosclerosis has been viewed as a “lipid-mediated” disorder and thus disease management focuses primarily on controlling the lipids, such as LDL-cholesterol. Yet, lowering lipid levels to recommended levels doesn’t protect most people from a cardiac event, indicating missing pieces in the puzzle. Mouse model research has shown that atherosclerosis is driven by certain immune cells that have gone rogue. Initially they are few in number. But as the disease progresses these harmful cells multiply and outcompete their “protective” counterparts, tilting the balance towards a severe outcome. Such “harmful” vs “protective” functional dichotomy is particularly evident in case of T cells, a highly specialized immune cell.

As a first in human atherosclerosis research, I propose to use an optimized set of immunological assays to identify disease-associated “rogue” T cells in human blood and track their functional evolution over the course of the disease. When combined with cutting-edge sequencing technologies, these assays can generate molecular “fingerprints” of the harmful and the protective cell-types. The results could help inform the development of a blood-based screening strategy for heart disease.

Six-Month Project Update

It is becoming increasingly evident that heart disease progression is driven by immune cells, particularly T cells. My goal is to develop assays that can detect—and reveal—the biological identities of harmful T cells.

Normally, T cells respond only to foreign molecules, or “antigens,” such as molecules on bacteria and viruses. But in case of heart disease, some rogue T cells recognize self-antigens, i.e., molecules that are present in our own bodies. Researchers studying mouse models have shown that the protein backbone of “bad” LDL cholesterol, called apolipoprotein B, is a major cause of heart-disease in subjects with these harmful immune responses. Therefore, I examined whether human T cells also respond to this self-antigen. For my initial analysis, I chose to study blood samples from young and middle-aged donors not diagnosed with heart disease.

The fact that my assays are able to detect heart-disease related inflammatory T cell responses in the general population signifies the tremendous potential of this workflow in evaluating early signs of the disease. My study also reveals that rogue T cells identify specific sites called “epitopes” in the human apolipoprotein B candidate antigenic protein. Identifying this epitope panel marks the first step towards the development of an immune-based diagnostic screening tool for disease-related T cell responses.