Breakthroughs in medical science rarely burst on the scene. Behind every advance is years of work by dogged researchers who nurtured the seed of idea until it flowered, bore fruit and materialized into a better treatment, device or therapy for patients. Here is where those seeds start: More than a dozen projects related to cancer, cell structures, genetics and epigenetics, immunology and tissue regeneration were funded in this year’s Mayo Clinic Center for Biomedical Discovery 2019 Pilot Grants. The award provides focused, one-time funds for imaginative proof-of-principle studies or model-development needed to lay the foundation for future efforts.
Bone marrow fat (adiposity) is a hallmark of aging bones. Rising levels are correlated with reduction in bone density, which can lead to osteoporosis. Jennifer Westendorf, Ph.D., and team will clarify the role of adipose tissue in bone marrow and discover the pathways that encourage this yellow marrow to form. They will examine the composition of the marrow adipose tissue and a genetic regulator, called histone deacetylase 3, for its role in changing gene expression and cellular composition of bone marrow.
Cellular Antennae and a Rare Disease
With this new funding, Haitao Wang, Ph.D., and Jinghua Hu, Ph.D., will investigate how a cellular “antenna,” or cilium, determine how stem cells differentiate into muscle, connective tissue, or bones. The knowledge will help us to understand many degeneration diseases that currently have no treatment or cure.
Inflammatory Bowel Disease
This team will investigate the interaction between cellular metabolism and intestinal macrophage functions. They are investigating what role, if any, this interaction plays in controlling gut inflammation as seen in inflammatory bowel disease. Study investigator W K Eddie Ip, Ph.D., hopes to use this work to further understand how inflammatory bowel disease begins and what therapeutic targets might be on the horizon.
Fibrosis is a serious disease process characterized by uncontrolled internal scarring. Researchers Daniel Tschumperlin, Ph.D., Christopher Evans, Ph.D., and Robert Vassallo, M.D., are hoping to better understand the biology of fibrosis and how loss of important transcription factors affects the disease process. The team will investigate the transcription factor CEBPA and develop a new approach to enhancing its expression in lung epithelial cells to reduce fibrosis.
The researchers on this project are looking at how the liver heals after injury. They hope this knowledge will improve how patients undergoing surgery of the liver recover, and provide ideas on how to support liver regeneration. The researchers on this project are Rory Smoot, M.D., Patrick Starlinger, M.D., Ph.D., and Gregory Gores, M.D. They report that preliminary data suggests a role for the Yes-associated protein (YAP) and will explore if SHP2 inhibition increases YAP activation in a mouse model and if increased YAP activity results in accelerated liver regeneration in a mouse model.
With this project, researchers hope to improve quality of life and life expectancy in Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) by establishing a model system of cardiomyopathy. The researchers on this project — Tamas Kozicz, M.D., Ph.D., Timothy Nelson, M.D., Ph.D., Eva Morava-Kozicz, M.D., Ph.D., — will perform deep phenotyping to improve knowledge of pathology and complete high-throughput drug screening to identify possible therapies.
Cancer, Cancer Treatment and Cancer Treatment Side-Effects
One cancer-related effort will examine cytotoxic T lymphocytes and their role in immunotherapy. Two projects were funded in this area. One will investigate a protein called NKG7, identified by the research team as being associated with a lack of benefit in immunotherapy. Led by Haidong Dong, M.D., Ph.D., and Daniel Billadeau, Ph.D., the team will develop antibodies to detect NKG7 in patient samples and generate cell lines without the genetic ability to produce NKG7. In a second project, Dr. Dong, Roxana Dronca, M.D., and Yiyi Yan, Ph.D., will create a mouse model to examine the role of NKG7 in the ability of CD8-positive T cells to respond during anti-programmed death ligand 1(PD-L1) therapy. The researchers hope that by clarifying the role of mediators to cytotoxicity, they can improve patient response to PD-1 checkpoint blockade immunotherapy.
Also related to immunotherapy, a pilot grant was awarded to Frank Sinicrope, M.D., and Bo Qin, Ph.D., to study the association of the immune checkpoint protein PD-L1 with a cell-death regulator called BIM in colorectal cancer cells. They will examine if PD-L1 controls the level of BIM protein via an enzyme known as an E3 ligase.
Funding was also provided to establish a mouse model that will examine long noncoding RNA. The researcher leading the project, Wenqian Hu, Ph.D., and his team report that these RNA are important during the production of red blood cells and regulation of the stem cells that develop into blood cells. The team will focus on a specific RNA, called Dleu2, and hope that the mouse model will reveal how it regulates normal blood cell formation as well as novel insights into the development of chronic lymphocytic leukemia.
In another project aimed at blood stem cells, researchers will look at the possibility of predicting the evolutionally trajectories from normal to acute myeloid leukemia and myelodysplastic syndromes, based on variants of a germline zinc finger transcription factor called GATA2. This factor is critical in formation of the stem cells that develop into blood cells. This project will be undertaken by Mrinal Patnaik, M.B.B.S.; Ryan Carr, M.D., Ph.D.; Terra Lasho, Ph.D.; and Moritz Binder, M.D.
A pilot grant to examine chemotherapy-induced nerve damage was awarded to Christopher Groen, Ph.D., Jewel Podratz, and Anthony Windebank, M.D. In a Drosophila model, the researchers have identified genetic variations in mitochondria genes that provide resistance to neuropathy (read about their work in Discovery’s Edge). The award will allow them to examine changes in mitochondria that confer that resistance novel 3D electron microscopy available through the Microscopy and Cell Analysis Core Facility. If successful, their work has the potential to establish a direct link between mitochondrial health and chemotherapy-induced peripheral neuropathy outcomes.
To study the inherent genetic instability of cancers, a grant was awarded to Larry Pease, Ph.D., and Keith Robertson, Ph.D., who will focus on genetic markers in breast cancer. In their work to date, they’ve detected a form of genetic instability that pervades the genome of breast cancer cells and allows tumors to evade homeostatic cell growth regulation and tumor recognition by the immune system. To look into the nature of genetic changes allowing tumor evolution, the researchers will develop a mouse model of spontaneous breast cancer that can be targeted specifically by tumor suppressing immune cells, enriching for locus-specific modifications in HER2 gene expression in tumor cells escaping from tumoricidal immune attack.
For more information about Mayo’s Center for Biomedical Discovery or past awardees, visit the Center for Biomedical Discovery website.
Tags: Anthony Windebank, basic science, cancer, cancer genomics, Center for Biomedical Discovery, Christopher Evans, Christopher Groen, Daniel Billadeau, Daniel Tschumperlin, discovery research, Eva Morava-Kozicz, fibrosis, Frank Sinicrope, Gregory Gores, Haidong Dong, Haitao Wang, IBD, inflammatory bowel disease, Jinghua Hu, Keith Robertson, Larry Pease, leukemia, liver disease, Mrinal Patnaik, neuropathy, News, osteoporosis, Patrick Starlinger, rare disease, Robert Vassallo, Rory Smoot, Roxana Dronca, Ryan Carr, Tamas Kozicz, Terra Lasho, Timothy Nelson, W K Eddie Ip, Wenqian Hu, Yiyi Yan