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Written by: Christina Crowe and Hannah Buckelew
Media contact: Anna Jones

Stream RO1 fundingThis funding will be used to research multiple health conditions, including alcohol-related liver disease, Alzheimer’s disease, breast cancer, heart failure, inflammatory bowel disease and Zhu-Tokita-Takenouchi-Kim syndrome.Researchers at the University of Alabama at Birmingham Department of Pathology recently received multiple R01 grants from the National Institutes of Health totaling more than $15 million in research funding.

Erin (Eun-Young) Ahn, Ph.D., Shannon Bailey, Ph.D., Shu Chen, Ph.D., Robin Hatton, Ph.D., Selvarangan Ponnazhagan, Ph.D., Casey Weaver, M.D., and Adam R. Wende, Ph.D., from the UAB Marnix E. Heersink School of Medicine are the recipients of these awards. Each grant began this year and will continue for the next three to five years.

“This robust influx of funding reflects the caliber and commitment of our faculty to advance pathology through clinical and translational research,” said George Netto, M.D., Robert and Ruth Anderson Endowed Chair. “I am proud of our team members, who are committed to shaping the future of precision medicine through their dedication to research and making a positive impact on patients’ lives.” 

ZTTK Syndrome

Ahn, associate professor in the Division of Molecular and Cellular Pathology, has received $2 million in funding to research “Genetic and Molecular Basis of Hematopoietic Abnormalities in ZTTK Syndrome.” Zhu-Tokita-Takenouchi-Kim, or ZTTK, syndrome is a rare disease identified primarily in children that is characterized by intellectual disability, delayed motor-psycho development and multi-organ anomalies. It is caused by loss-of-function mutations in the SON gene, known as SON haploinsufficiency. The SON gene creates a DNA and RNA binding protein that is required for the body to grow and develop normally. Ahn has been studying the SON protein and gene since the early 2000s. Her work led to the discovery of ZTTK syndrome in 2016.  

Ahn’s recent studies have revealed that many children diagnosed with ZTTK syndrome experience blood disorders and immune dysfunction, which may lead to life-threatening sepsis. Hematopoietic stem cells are immature cells that can develop into all blood cell types to create a balanced number of cell types. Ahn suspects that ZTTK patients’ HSCs are causing an imbalance in cell lineage function as blood cells to support and protect the body. With this funding, Ahn’s team aims to delineate the mechanism underlying hematopoietic abnormalities in ZTTK syndrome.

Alcohol-related liver failure

Alcohol use remains a top 10 cause of preventable death, and alcohol-related liver disease is the top cause of death from alcohol use in the United States. One early and primary target of alcohol hepatotoxicity, which is fatty liver and inflammation, is the liver mitochondrion. The liver mitochondrion plays a role in oxidative metabolism, wherein oxygen is used to make energy from carbohydrates and fats to power liver function.  

Bailey, a professor in the Division of Molecular and Cellular Pathology, has received a $2.35 million grant for her project titled “Circadian and mitochondrial dysfunction in alcohol-related liver disease.” The five-year project will allow her research team to dig deeper into how chronic alcohol consumption disrupts daily changes in liver mitochondrial function. The main goals of this research include defining the roles of different molecular circadian clock genes in alcohol-induced mitochondrial dysfunction, and to test whether normalizing function of the molecular clock during alcohol consumption lessens mitochondrial damage and alcohol-associated liver disease.

Alzheimer’s disease

Chen, Ona Faye-Petersen Endowed Professor in the UAB Division of Neuropathology, received an R01 award in the amount of $3.67 million for his research titled “Peripheral Biomarkers for Early Diagnosis of Mixed Pathologies in AD/ADRD.” It may not be commonly known that the only definitive way to diagnose Alzheimer’s disease and related dementias is through autopsy of the deceased patient’s brain. With this grant, Chen will study how skin or bodily fluid-based biomarkers can be used to diagnose Alzheimer’s disease and related dementia diseases early on, allowing for earlier interventions for treatment and care.

A major problem with dementia and related diseases is the occurrence of overlapping symptoms, and not understanding the root cause of the diseases — making early diagnosis very difficult. Through his research, Chen hopes to develop a biomarker laboratory test that uses specimens from areas such as the skin, spinal fluid or inside of the nose to look for a cluster of proteins that may be indicative of the disease. The goal of this test is to allow for earlier detection of Alzheimer’s disease and related dementia, which can lead to better treatment options. 

Inflammatory bowel diseases

Hatton, an associate professor in the Division of Anatomic Pathology, and Weaver, the Wyatt and Susan Haskell Endowed Chair for Medical Excellence, have received a $3.6 million grant to research “Mechanisms Controlling the Development and Function of Intestinal Effector Treg cells.” Effector regulatory T cells, also known eTregs, help suppress inflammation in part by producing IL-10 — an anti-inflammatory and immunoregulatory protein. With this research, Hatton and Weaver plan to focus on the signals that direct development of these IL-10-producing cells with the long-term goal of identifying therapeutic targets that limit intestinal pathology in human inflammatory bowel disease.

Defects in IL-10 signaling are associated with IBD and Tregs are the main source of IL-10 in the gut. Therefore, Hatton and Weaver are investigating pathways that promote eTreg development.  In pre-clinical models, the research team found that these IL-10-expressing eTreg cells are effective in ending intestinal inflammation. Through this funding, Hatton and Weaver aim to define mechanism that amplify IL-10 expression by eTregs that can be used in IBD treatment.

Breast cancer

Ponnazhagan, a professor in the Division of Molecular and Cellular Pathology, has received a $1.7 million R01 grant for his research titled “Mechanisms and Therapeutic Targeting of Osteoimmune Functions of RANKL in Breast Cancer.” Current treatments for patients with breast cancer bone metastases have shown that targeting tumor cells alone is not sufficient for long-term survival, but a multi-faceted approach is needed to inhibit tumor cells in the bone that drive immunosuppression and tumor growth.

As breast cancer spreads throughout the bone, tumor cells interact with reactive stroma and immune cells in the microenvironment, which results in the production of cytokines and thereby causes changes in normal homeostasis of the skeletal and immune systems. A major protein that regulates this effect is nuclear factor kappa-B ligand, or RANKL. Thus, understanding the role of RANKL effects beyond its role in bone damage and developing targeted therapies to impair excess RANKL function will provide additional therapeutic options for breast cancer patients with bone metastasis.

Heart failure

Wende, an associate professor in the Division of Molecular and Cellular Pathology, received $2.3 million for his research titled “Novel Roles of PDK2 In Heart Failure: Regulation of Mitochondrial Nuclear Crosstalk Via Metabolic Regulation and Histone Acetylation.”

When heart failure due to high blood pressure occurs, the heart reduces its reliance on fats and begins to rely more on sugars, specifically glucose. While both fuels can be used by the powerhouse of the cell, also known as the mitochondria, fats are better at meeting the heart’s energy demands. The pyruvate dehydrogenase complex, or PDH, helps regulate the breakdown of fats and sugars in the mitochondria; however, another family of proteins known as the PDH kinases, or PDK, can restrict the breakdown of these fuels. Humans have four of these proteins, and three of them are expressed in the heart. Two of these, PDK2 and PDK4, can be induced through healthy activities such as exercise.

In pre-clinical models, Wende and his team found that, when PDK2 is genetically deleted, it improved survival and helped protect the heart. They also found that genetically deleting PDK4 worsened heart failure. Wende’s research will help them better understand whether PDK2 is a good target to prevent heart failure and why removing PDK4 worsened heart failure.