Posts tagged with "scientist"

New Scientific Study by Rice University Biochemists

Michael Stern and James McNew (Photo by Jeff Fitlow/Rice University)

Study: Early, late stages of degenerative diseases are distinct
Two-phase theory applies to diseases like Alzheimer’s, Parkinson’s, muscle atrophy

Rice University biochemists Michael Stern and James McNew have studied how neurodegeneration kills cells. They’ve conducted countless experiments over more than a decade, and they’ve summarized all they’ve learned in a simple diagram they hope may change how doctors perceive and treat degenerative diseases as varied as Alzheimer’s, Parkinson’s, and muscle atrophy.

In a study published this month in Molecular Psychiatry, McNew and Stern propose that degeneration, at the cellular level, occurs in two distinct phases that are marked by very different activities of protein signaling pathways that regulate basic cell functions.

“We would like clinicians and other researchers to understand that the two phases of degeneration represent distinct entities, with distinct alterations in signaling pathways that have distinct effects on disease pathology,” said Stern, a professor of biosciences at Rice. “In other words, we think that patients need to be treated differently depending on which phase they are in.”

Stern and McNew’s diagram shows how the activity of key cell-signaling proteins either increases or decreases at the onset of degeneration, ultimately bringing about oxidative stress. Oxidative stress then brings about the second phase of the condition, during which degeneration occurs, where the signaling proteins implicated in the first phase behave in a completely different way.

Because cells behave quite differently in the two phases, the research suggests patients in different phases of a disease may respond differently to the same treatment.

“The two phases of degeneration haven’t been previously recognized, so it hasn’t been understood, clinically, that you have two different populations of patients,” McNew said. “Today, they’re treated like one population, and we think this has confounded clinical trials and explains why some trials on Alzheimer’s have given variable and irreproducible effects. It would be like trying to treat all meningitis patients with antibiotics without realizing that there are two types of meningitis, one bacterial and one viral.”

Stern and McNew, professors of biochemistry and cell biology in Rice’s Department of BioSciences, became interested in the cellular processes of neurodegenerative disorders when they began studying hereditary spastic paraplegia (HSP) in the late 2000s. A rare disorder, HSP is marked by numbness and weakness in the legs and feet due to the progressive deterioration of neurons that connect the spine and lower leg.

These are some of the longest cells in the body, and starting with clues about structural defects that could cause them to degenerate, McNew and Stern used experiments on fruit flies to systematically piece together the biochemical domino effect that caused the neurons to progressively lose more and more function and eventually die. It had been thought that nerve damage could lead to muscle atrophy, but their studies found that muscle cells attached to the neurons started degenerating from the same type of biochemical cascade before the nerve cells died.

A key player in the cascade was a protein called TOR, a master regulator of cell growth and an essential protein for all higher-order life from yeast to humans. TOR acts like a knob, dialing growth up or down to suit the conditions a cell is experiencing. In some conditions, high growth is warranted and beneficial, and in other situations, growth needs to be dialed back so energy and resources can be conserved for daily chores, like the recycling or repair that take place during a process known as autophagy.

Some cancers highjack TOR to promote aggressive cell growth, and increased TOR activity has also been implicated in neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases and in diseases marked by muscle atrophy. After compiling evidence about how TOR and several other signaling proteins behaved in neurodegeneration, McNew and Stern won a grant from the National Institute of Neurological Disorders and Stroke in 2018 for experiments to investigate signaling pathway changes that occur in the early stages of degeneration.

“At the time, we thought there might be a late phase during which degeneration actually occurs, but we didn’t propose any experiments to test that,” Stern said. “In the new paper, we’re explicit about the existence of a late phase. We propose mechanistically why degeneration occurs only during this phase, and cite abundant research in support.”

Stern said the two-phase process described in the study “is the basic engine that drives most or even all forms of degeneration forward. However, in addition, there are also inputs whose role is to specify how fast the engine turns over.”

To understand neurodegeneration, it’s critical to understand how those inputs work, he said. For example, insulin resistance plays a well-known role in driving Alzheimer’s disease, and in the study, McNew and Stern describe how it does that by accelerating progression through the early phase.

“Similarly, our data suggests that decreases in synaptic transmission, as occurs in our HSP insect model, likewise triggers degeneration by accelerating progression through the early phase,” McNew said. “Our NIH grant was funded so that we could learn the mechanism by which that occurs.”

Now that they clearly understand that two phases of degeneration exist, Stern said he and McNew would like to carry out more experiments to see how the effects of specific genes on degeneration are altered when they are activated in the early and late phases.

“What we would like to do in the last two years of the grant is to obtain data to test some of the predictions we have made, which will help determine if the ideas we have presented are likely to be correct,” Stern said.

The research was supported by the National Institutes of Health (R01-NS102676).

Therapies Developed to Reduce Lung Fibrosis

A new treatment option for lung fibrosis is being developed by Purdue University scientists. Lung fibrosis has been a concern for COVID-19 patients.

People with idiopathic pulmonary fibrosis (IPF) have a life expectancy of fewer than five years. Fibrotic diseases cause organ failure that leads to about 45% of all deaths in the United States. Existing therapies do little to slow progression.

Now, Philip S. Low, Purdue’s Ralph C. Corley Distinguished Professor of Chemistry and Presidential Scholar for Drug Discovery, has led a team to develop two targeted therapies for people with IPF. The two different therapeutic approaches are published in Science Translational Medicine and EMBO Molecular Medicine.

“This is a horrible disease that claimed the lives of my next-door neighbor and a good friend’s wife,” Low said. “We developed two targeted therapies that allow us to use powerful drugs with high toxicities because we specifically deliver them to diseased cells without harming healthy ones.”

The first of the Purdue team’s novel targeted molecules is designed to slow fibrosis and extend life. The second IPF therapy suppresses fibrosis-inducing cytokine production.

The two therapies will be moving into human clinical trials within the next several months. The developments come as a number of people with COVID-19 or who have recovered from COVID-19 experience lung fibrosis or other related conditions.

The therapy technologies are licensed through the Purdue Research Foundation Office of Technology Commercialization and optioned to MorphImmune, a startup co-founded by Low. For more information on licensing a Purdue innovation, contact the Office of Technology Commercialization at otcip@prf.org.

About Purdue Research Foundation

The Purdue Research Foundation is a private, nonprofit foundation created to advance the mission of Purdue University. Established in 1930, the foundation accepts gifts; administers trusts; funds scholarships and grants; acquires property; protects Purdue’s intellectual property; and promotes entrepreneurial activities on behalf of Purdue. The foundation manages the Purdue Foundry, Purdue Office of Technology Commercialization, Purdue Research Park, Purdue Technology Centers and University Development Office. In 2020, the IPWatchdog Institute ranked Purdue third nationally in startup creation and in the top 20 for patents. The foundation received the 2019 Innovation and Economic Prosperity Universities Award for Place from the Association of Public and Land-grant Universities. For more information on licensing a Purdue innovation, contact the Purdue Office of Technology Commercialization at otcip@prf.org. For more information about involvement and investment opportunities in startups based on a Purdue innovation, contact the Purdue Foundry at foundry@prf.org.

About Purdue University

Purdue University is a top public research institution developing practical solutions to today’s toughest challenges. Ranked the No. 5 Most Innovative University in the United States by U.S. News & World Report, Purdue delivers world-changing research and out-of-this-world discovery. Committed to hands-on and online, real-world learning, Purdue offers a transformative education to all. Committed to affordability and accessibility, Purdue has frozen tuition and most fees at 2012-13 levels, enabling more students than ever to graduate debt-free. See how Purdue never stops in the persistent pursuit of the next giant leap at purdue.edu.

Writer: Chris Adam, cladam@prf.org
Source: Philip Low, plow@purdue.edu

Suraj U. Hettiarachchi, Yen-Hsing Li, Jyoti Roy, Fenghua Zhang, Estela Puchulu-Campanella, Spencer D. Lindeman, Madduri Srinivasarao, Konstantin Tsoyi, Xiaoliang Liang, Ehab A. Ayaub, Cheryl Nickerson-Nutter, Ivan O. Rosas and Philip S. Low

rice university, 360 MAGAZINE, health, study, leukemia

Cocktail proves toxic to leukemia cells

Rice University, MD Anderson research points toward better personalized therapy

A combination of drugs that affect mitochondria — the power plants inside cells — may become the best weapons yet to fight acute myeloid leukemia, according to Rice University researchers.

A study led by Rice bioscientist Natasha Kirienko and postdoctoral researcher Svetlana Panina found that mitocans, anti-cancer drugs that target mitochondria, are particularly adept at killing leukemia cells, especially when combined with a glycolytic inhibitor, while leaving healthy blood cells in the same sample largely unaffected.

Their open access paper, a collaboration with the University of Texas MD Anderson Cancer Center, appears in the Nature journal Cell Death & Disease. The research could lead to new ways to personalize treatment for patients with leukemia.
“We started with the idea of finding an underlying connection between types of cancer and their sensitivity to specific kinds of chemotherapeutics, mitochondria-targeting drugs,” Kirienko said. “Our bioinformatic analysis, which included 60 cell lines from nine different cancer types, showed that leukemia cells are particularly sensitive to mitochondrial damage.”

The researchers exposed the cell lines to multiple known mitocan molecules. They found low doses of a mitocan/glycolytic inhibitor cocktail killed all of the leukemia cell lines they tested at concentrations lower than what was necessary to kill healthy cells. Conversely, they reported that solid tumor cells, like ovarian cancers, proved highly resistant to mitocans. Glioblastoma cells were sensitive to mitocans, but unfortunately more resistant than healthy blood cells.

In their best experimental results, 86% of targeted leukemia cells were killed, compared to only 30% of healthy blood cells. “A number of drugs currently used in the clinic have some cancer preference, but here we’re talking about a five-fold difference in survival,” Kirienko said.
The researchers also showed a significant correlation between how efficiently mitochondria can turn energy from incoming oxygen into useful adenosine triphosphate (ATP) and how resistant they are to treatment.

“The more efficient they are, the more resistant they will be to mitochondria-targeting drugs,” Kirienko said. “If this holds true, doctors can perform a relatively simple test of this specific parameter of mitochondrial health from a patient’s sample and predict whether the treatment would be effective.”
Panina said computational models led them to think the glycolysis pathway could be enlisted to help mitocans. “Glycolysis also provides ATP, so targeting that will decrease energy as well as block the precursor for energy production in mitochondria, which mitocans will exacerbate further,” she said. “It led us to believe this combination would have a synergistic effect.

“Cancer cells are usually more metabolically active than normal cells, so we predicted that they be might be more sensitive to this combined strike, and they are,” Panina said.

Kirienko said a presentation of the research she and Panina gave at MD Anderson’s recent Metabolism in Cancer Symposium drew a large response. “People were very interested, and they immediately started asking, ‘Did you test my favorite drug or combination?’ and ‘Are you going to test it in a wider panel of cancers?’”

That work is well underway, Panina said. “We’re currently doing high-throughput screening of these potential synergistic drug combinations against leukemia cells,” she said. “We’ve gone through 36 combinations so far, building landscapes for each one.”
“And we found some that are more effective than what’s reported in this paper,” Kirienko added. “But we’ve also found some that are antagonistic — two drugs that negate each other’s effects — so it’s also important to know what therapeutic cocktails should not go together.”

Co-authors of the paper are postdoctoral fellow Natalia Baran; Marina Konopleva, a physician-scientist and professor in the Department of Leukemia at MD Anderson; and Rice graduate student Fabio Brasil da Costa. Kirienko is an assistant professor of biosciences.
The Cancer Prevention Research Institute of Texas, the Welch Foundation and the National Institutes of Health supported the research.

Read the paper at http://www.nature.com/articles/s41419-019-1851-3.pdf.

This news release can be found online at http://news.rice.edu/2019/10/31/cocktail-proves-toxic-to-leukemia-cells/

Follow Rice News and Media Relations via Twitter @RiceUNews.

Related materials:


Kirienko Lab: http://kirienkolab.rice.edu/index.html
Marina Konopleva: http://faculty.mdanderson.org/profiles/marina_konopleva.html
Rice Department of BioSciences: http://biosciences.rice.edu
Wiess School of Natural Sciences: http://naturalsciences.rice.edu

MENTALLIGENCE: A New Psychology of Thinking 

As the headlines warn of a world seemingly taking steps backward, behavioral scientist Dr. Kristen Lee shares a new psychology of thinking to move you forward with a new mindset and patterns of behaviors that inspire connection, collaboration, proactivity, and creativity.

Based on twenty years of clinical practice and neuroscientific research, Dr. Kristen Lee teaches us how to see the world―and its most difficult situations―through a series of different lenses, to steer our brains to cultivate “upward spiral habits.” This is what psychologists call “The Good Life”—living mindfully and consciously regardless of what is going on around us. Instead of falling into common behavioral traps which lead to perpetual patterns of shutting down, numbing out, binding up, and staying stuck.

MENTALLIGENCE: A New Psychology of Thinking helps us find the thinking and behavioral agility to work toward better outcomes for all.

* Rethink the many forms of social conditioning to reduce mindlessness, ignorance, and compulsions towards insularity, hatred, bias, and fear.

• Advance human progress through empathy, curiosity, familiarity, and unconditional regard.

* Avoid the 4 common downward spiral behavioral traps: Sleepwalking, Perfectionism, Centricism, and Lockdown.

* Learn how to become impact-driven instead of performance-obsessed.

* Discover how to work with “collective efficacy” that is less I-focused and more we-focused, to facilitate positive social impact at a time when it’s desperately needed.

• Refuse to be held hostage by bigotry, ignorance and polarization, and instead link arms in solidarity to find common ground and get to the Good Life together.

About the Author:

Dr. Kristen Lee, EdD, LICSW, is a recovering perfectionist and clinician, researcher, educator and activist with twenty-two years of experience. She is lead faculty for Behavioral Science at Northeastern University in Boston and author of Indie Book Award’s 2015 Motivational Book of the Year, Reset: Make the Most of Your Stress. To learn more follow on social media (Twitter, Instagram, Facebook, Snapchat).

Available wherever books are sold or to order directly from the publisher contact:

(800) 441-5569 or www.hcibooks.com.

MENTALLIGENCE: A New Psychology of Thinking

Kristen Lee, EdD, LICSW

February 2018

ISBN-13: 9780757320576

$15.95