Arkansas medical researchers receive grants

NHI awards $1.6M for pathogen-borne disease studies

The National Institutes of Health recently awarded an additional $1.6 million to researchers at the University of Arkansas for Medical Sciences (UAMS) to continue a 14-year effort aimed at gaining a deeper understanding of the fundamental principles governing intracellular membrane traffic – a crucial process occurring in every human cell.

Intracellular traffic plays a pivotal role in the transportation of proteins and other macromolecules to diverse cellular locations, both within and outside the cell. It serves as a vital mechanism for maintaining cellular homeostasis and significantly influences the interactions between cells and their surrounding environment.

Vladimir Lupashin, Ph.D., a professor in the UAMS College of Medicine Department of Physiology and Cell Biology and the primary investigator, said comprehension of these mechanisms serves as a crucial foundation for developing effective treatments for a wide range of diseases, including cystic fibrosis, Parkinson’s disease and Alzheimer’s disease. Moreover, it plays a significant role in understanding and addressing other conditions such as Amyotrophic Lateral Sclerosis (ALS), and various forms of cancer and diabetes. By unraveling the intricate workings of intracellular membrane traffic, researchers aim to uncover novel therapeutic targets and strategies to combat these debilitating illnesses.

Lupashin’s laboratory has already made several scientific contributions that have resulted in the publishing of more than 80 original papers in high-profile scientific journals.

“We have pioneered the functional analysis of the Conserved Oligomeric Golgi (COG), an evolutionarily conserved protein complex critical for membrane trafficking and protein modifications in the Golgi apparatus,” he said, describing the Golgi as “the central hub for protein modification and sorting within cells. It plays a pivotal role in a process known as glycosylation, where highly complex sugars or glycans are added to proteins.”

Mutations affecting the COG complex can disrupt the normal functioning of the Golgi apparatus, leading to a group of rare diseases known as Congenital Disorders of Glycosylation (CDG). CDG encompasses a diverse spectrum of disorders, each characterized by specific symptoms and complications, including developmental delays, neurological impairments, organ dysfunction, and various other systemic abnormalities. By understanding the impact of COG complex mutations on Golgi function and glycosylation, researchers aim to uncover insights into the underlying mechanisms of CDG and develop potential therapeutic interventions to alleviate its associated symptoms and improve patients’ quality of life.

Additionally, Lupashin highlighted that the COG complex, a critical component of intracellular membrane traffic, can be exploited by various pathogens such as viruses, pathogenic bacteria, and toxins. However, the precise mechanisms by which these diverse groups of pathogens evolved to depend on COG function remain unclear.

“Understanding the molecular basis of COG-pathogen interactions will allow us to develop the strategies to protect cells and organisms from pathogen-borne diseases,” Lupashin said.

The R01 renewal totals $1,638,172 and enables the research to continue through March 31, 2027. The original five-year grant has been continuously renewed in four-year increments. In total, Lupashin has received $6,270,227 from the NIH for this research.

National Cancer Institute awards $2.26M for multiple myeloma study

University of Arkansas for Medical Sciences (UAMS) researchers Teresita Bellido, Ph.D., and Jesus Delgado-Calle, Ph.D., recently received a five-year, $2.26 million continuation award from the National Cancer Institute.

Bellido is a professor and chair of the Department of Physiology and Cell Biology in the UAMS College of Medicine, while Delgado-Calle is an associate professor in the department.

The R01 grant, originally awarded in March 2017, supports the study, “Contribution of Osteocytes to the Musculoskeletal Effects of Multiple Myeloma.”

The overall goal of the study is to determine the role of osteocytes, the most abundant type of bone cells living within mineralized bone, in multiple myeloma tumor microenvironment, which consists of the environment around a tumor, including nearby blood vessels and healthy immune cells. The current grant will use genetic and pharmacological approaches to investigate the contribution of osteocyte-derived FGF23 on multiple myeloma growth, the associated bone disease, and resistance to chemotherapy. Results from these studies will pave the road for the development of new therapeutic interventions targeting osteocytes.

“It is exciting to continue working on this project. We were very productive in the first cycle of this grant and established a paradigm shift in the field of cancer in bone by showing that osteocytes, cells buried within the bone mineral, are part of the niche that regulates multiple myeloma cancer growth,” said Bellido.

“These funds will allow us to study the consequences of interrupting the communication between myeloma cancer cells and osteocytes on tumor growth, bone disease and resistance to chemotherapy,” Delgado-Calle said.

The continuation award, which runs through June 2028, also allows for an investigation of the impact of Burosumab, an anti-FGF23 neutralizing antibody, on different aspects of multiple myeloma disease and how it interacts with other treatments commonly used to treat myeloma patients, Delgado-Calle added.