Genetically Modifying Adipocytes to Increase Fat Burning and Improve Metabolic Function as a Potential Therapy for Type 2 Diabetes
Researcher Spotlight: Sarah Nicoloro
Date Posted: jueves, marzo 24, 2022
The Czech lab is using genetic engineering to investigate a therapeutic approach to type 2 diabetes. They appreciate the important role that adipocytes or fat cells play in the development and progression of diabetes. In a collaborative project with the Corvera Lab, they’re editing genes of adipocytes to increase fat burning and improve their metabolic function as a potential therapy.
Sarah Nicoloro received her Bachelor of Science in Biology from UMass Lowell. When she was in high school, her goal was to attend medical school and become a physician. “I always wanted to help people,” she said. “The research we’re doing has the potential to help lots of people with diabetes and obesity, it’s just a different way of doing it. It’s very exciting.”
A recently published study in Nature Communications presents data obtained by Sarah and a team of scientists who removed cell samples from humans, converted white adipocytes into brown-like cells in the lab, reproduced and multiplied those cells, and transplanted them into “humanized” mice to test the therapeutic approach. Their findings indicate the process enhanced and improved glucose metabolism. The Department of Defense has extended their grant through 2024 to fund pre-clinical studies using non-human primate cells.
CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease
Tsagkaraki E, Nicoloro SM, DeSouza T, Solivan-Rivera J, Desai A, Lifshitz LM, Shen Y, Kelly M, Guilherme A, Henriques F, Amrani N, Ibraheim R, Rodriguez TC, Luk K, Maitland S, Friedline RH, Tauer L, Hu X, Kim JK, Wolfe SA, Sontheimer EJ, Corvera S, Czech MP. Nat Commun. 2021 Nov 26;12(1):6931. doi: 10.1038/s41467-021-27190-y. PMID: 34836963
A possible scenario for the therapy could be to obtain a pool of cells collected from heathy donors, similar to blood donation. Those cells would be replicated in the lab and engrafted into to people in need.
“Sarah is an amazing lab colleague and leader in our group. Her efforts have been critical to our success,” said Michael P. Czech, PhD, the Isadore and Fannie Foxman Chair in Medical Research and professor of molecular medicine at UMass Chan Medical School. “She brings outstanding intellectual input into her projects, superb management skills and terrific collegiality in enriching our learning environment.”
The Road from College to the Research Lab
Sarah spent the summer between her junior and senior years at UMass Lowell interning at a Boston-based biotechnology company focused on cell xenotransplantation technology, called Diacrin. That’s where she first met Dr. Czech, who was on their scientific advisory board. He was the specialist advising on general scientific principals and specifically the diabetes program.
It was during that internship that Sarah’s plans changed from medical school, to instead focusing on a research career. Her internship led to a full-time position immediately after graduation.
After a few years working at Diacrin, she moved to Central Massachusetts and got a job at UMass Chan Medical School as a research assistant. She worked with pediatric endocrinologist Rosalind Brown, investigating thyroid diseases by using rat fetal thyroid cells. Grant funding expired after one year, so Sarah looked for other opportunities on campus. There was an opening in the Czech Lab.
Joining the Czech Lab in 1998
Sarah’s first project in the Czech Lab was assisting in a screen to identify unique genes that increase during adipogenesis by performing northern blot analysis, cloning and sequence analysis.
“At the time, the Human Genome Project was not yet complete,” said Sarah. “There was still a lot of unknowns about genes and proteins compared to today.”
The lab’s focus during the early 2000’s was to learn about the interactions taking place within adipocytes. They were particularly interested in insulin signaling and GLUT4 trafficking. GLUT4 is the principal glucose transporter protein responsible for insulin-regulated glucose uptake in fat and muscle cells. Some of that work employed a new Nobel Prize winning technology called RNAi, discovered by Craig Mello and Andrew Fire. “RNAi was a novel and specific way to knock-down genes in cells and was a complete game-changer,” said Sarah.
Glucan-Encapsulated siRNA Particles (GeRPs)
The Czech lab recognized the potential of RNA interference (RNAi) as a therapeutic tool for inflammation and metabolic disease including obesity and diabetes. They developed siRNA screens and identified the protein coding genes Map4k4 and RIP140 as metabolic regulators. In a successful collaboration with Gary Ostroff, Sarah was part of a team of scientists who developed a novel small interfering RNA (siRNA) delivery system. GeRPs are made from baker’s yeast that have been treated to remove all proteins except the glucan shell. The Glucan shell was then used to encapsulate siRNA to deliver to cells in vivo
“That was a very exciting time,” said Sarah. “Not only was it successful, interesting and fun, but the GeRPs technology taught us about the difficulty of targeting specific cells for delivery. Since there is no known target specific to fat cells, it led to our current project of genetically altering adipocytes outside of the body, then putting them back in.”
People Matter Most
For more than 20 years Sarah has worked on many different projects, but her fondest memories include the people she’s worked with. “Our lab has attracted and produced world-class scientists,” she said. “We’ve had people join the lab as students and leave with their PhD. Today, those scientists are part of both the academic setting and industry (pharmaceutical and biotech) labs. Some run their own successful laboratories in both venues. It’s been incredibly rewarding to teach them and to learn from them. It’s such a collaborative atmosphere.”
She credits Dr. Czech as a mentor, manager and teacher.
About Sarah
Sarah was born in Montreal. Her parents are British and moved from Scotland to Montreal in the late 1960’s. They eventually settled in Mississauga in the Canadian province of Ontario. Her father worked in the cargo shipping business and the family relocated to Beverly, MA during her senior year of high school.
All of Sarah’s relatives live in Scotland and Australia. She visited Australia once but spent entire summers in Scotland growing up. Another fond childhood memory are the sailings that the family took onboard cargo ships during her elementary and middle school vacations. “We were the only guest passengers on board,” she said. “They even filled up the pool for us with sea water. We would eat with the crew and go into the engine room. It was so cool!”
Those ships made stops at southern U.S. ports around the Gulf of Mexico and they also sailed down the Mississippi River. It’s easy to understand why she has a love of traveling as an adult.
Favorites
- Book: The Secret Life of Bees
- Movie: All of the Star Wars films
- Restaurant: Joey’s Bar & Grill in Worcester
- Sports Team: New England Patriots
- Hobbies: Cycling, photography and spending time with her three children and wonderful friends & family
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