With nearly 30 million Americans suffering from kidney disease, and treatment of kidney disease accounting for approximately 20 percent of the annual Medicare budget, it’s fair to say that Dr. Sandeep Mallipattu and his colleagues in Stony Brook Medicine’s Division of Nephrology in the Department of Medicine have their work cut out for them.
Fortunately, in his first year since being formally invested as the Dialysis Clinic, Inc. (DCI)-Martin Liebowitz Endowed Professor of Nephrology, Dr. Mallipattu has been quite busy living up to the legacy of the professorship’s namesake, Dr. Martin Liebowitz, who exemplified the highest level of dedication to medical education, patient care, and kidney disease research over the course of more than 30 years at Stony Brook. Most notably, Dr. Mallipattu is working to identify molecular mechanisms that could play a key role in fighting the most common types of kidney disease, and which might even help open the door to one day building a kidney.
“Throughout his career at Stony Brook, Dr. Mallipattu has epitomized excellence as a physician, biomedical scientist, educator, mentor and leader,” said Ken Kaushansky MD, Dean of the Renaissance School of Medicine at Stony Brook University and Vice President of Health Sciences. “His work as the DCI-Liebowitz Endowed Professor is already showing very promising results and could lead to real breakthroughs for patients here at Stony Brook and around the world.”
Thus far, Dr. Mallipattu’s research has centered around a group of proteins called Krüppel-like Factors, which regulate gene expression that contributes to kidney function.
“There are thousands of genes that are critical to the function of the kidney,” Dr. Mallipattu explained. “These Krüppel-like Factors (KLFs) serve as master regulators of these genes and changes in expression or activity of these critical molecules can dramatically alter kidney function, resulting in kidney injury. What we’ve been doing in the lab is trying to understand the precise role of these KLFs in various types of kidney diseases,” Dr. Mallipattu explained. “With that understanding, we can determine which specific factors might be targeted as a therapeutic to help prevent and treat various kidney diseases.”
Over the course of Dr. Mallipattu’s studies, one particular factor, referred to as KLF15, has emerged as a promising target for treatment. His laboratory has demonstrated that KLF15 protects podocytes from injury, which are cells that enable the kidney to perform its function as a filter. Given that dysfunction of the filtration barrier is the most common cause of kidney disease, determining whether and how KLF15 can be activated to protect the filtration function could be critical to advancing new groundbreaking treatments.
“Podocytes are very critical for maintenance of the filtration barrier,” Dr. Mallipattu said, “but they’re very similar to neurons in the sense that once you lose podocytes, your body can’t regenerate them. The induction of KLF15 expression specifically in these cells actually prevents the loss of these cells in models of kidney injury.”
In the coming year, Dr. Mallipattu plans to make investments to fine-tune the potential approaches to stimulate KLF15 and protect kidney filtration function. Working with a chemist from the Mount Sinai Health System, Dr. Mallipattu aims to identify the top chemical compounds that can be translated to clinical use to activate KLF15, but that’s just the beginning.
The real “pie in the sky” goal, according to Dr. Mallipattu, goes beyond protecting kidneys. It’s about building them.
Using transcription factor biology – including the Krüppel-like factors that he has been studying — Dr. Mallipattu and his colleagues have the technology in their lab to harvest cells from a patient and generate various types of new kidney cells at the microscopic level. These healthy cells can be grown in a petri dish with some organization into 3D structures called organoids, but the scientific community will need to figure out how to organize the cells into a more useful structure before they can be used to treat patients.
“At Stony Brook, we are working on groundbreaking research to combine these organoids in a petri dish with what we call biological scaffolds,” Dr. Mallipattu explains, “to organize the cells into a structure that can be implanted. By promoting self-assembly of these newly generated cells on biological scaffolds, we hope to build a human kidney suitable for transplantation.”
Dr. Mallipattu’s team aims to explore the use of two different types of biological scaffolds in partnership with colleagues from engineering and other key disciplines through Stony Brook’s new Institute for Engineering Driven Medicine (IEDM), to be housed in the upcoming Institute for Discovery and Innovation in Medicine and Engineering (I-DIME) building. The first type will involve three-dimensional printed structures made by biomedical engineers. The other source will use natural donated kidneys that Dr. Mallipattu hopes to ‘reprogram’ through advances in regenerative medicine.
“One problem we hope to address is that more than 3,000 donated kidneys are discarded every single year,” Dr. Mallipattu explains, “either because of the poor quality of the kidney or because they are not enough of a biological match to be transplanted. But if our research is successful, we will be able to ‘decellularize’ these kidneys to remove the cells, and then ‘recellularize’ them with the healthy cells that we’re generating. These ‘reprogrammed’ kidneys — all-natural scaffolds — will be better than anything we could 3D-print in a lab, and could potentially serve to model kidney disease, and possibly be suitable for eventual transplantation.”
For an ambitious endeavor like this — which earned Dr. Mallipattu a place among the top finalists for the Stony Brook Foundation’s Discovery Prize in April — an endowed professorship is all but essential, because of the flexibility the endowment offers to pursue a project that is not expected to yield immediate results.
“This type of project is something that is very difficult to secure funding from an extramural source,” Mallipattu said, “because it’s not something you’re going to be able to do over two or three years. It’s going to take some time. The idea is that we can use dependable funds from DCI’s endowment year after year, to generate preliminary data and establish proof of concept.”
The research Dr. Mallipattu and his colleagues are pursuing marks an exciting chapter in the long and fruitful relationship between Stony Brook Medicine and DCI. Building on years of partnership, DCI created the endowed professorship in 2014 to provide Stony Brook’s Division of Nephrology with essential, ongoing funding to recruit and retain pioneering faculty researchers like Dr. Mallipattu. Endowed professorships are a longstanding tribute to the donors who establish them, and a key resource to help Stony Brook Medicine push the boundaries of medical knowledge and pursue new and better treatments.
“The partnership between Stony Brook Medicine and DCI has supported powerful research at Stony Brook for years,” said Vincent Yang, MD, PhD, Simons Chair of Medicine. “With this ongoing support from DCI’s special endowment in nephrology, the next chapter of our partnership is full of tremendous promise, and I can’t wait to see where it leads.”