Breaking News
December 12, 2018 - People who eat red meat have high levels of chemical associated with heart disease, study finds
December 12, 2018 - New method uses water molecules to unlock neurons’ secrets
December 12, 2018 - New computer model predicts prostate cancer progression
December 12, 2018 - More Illnesses From Tainted Romaine Lettuce Reported
December 12, 2018 - Aspirin could reduce HIV infections in women
December 12, 2018 - Sacrificial immune cells alert body to infection
December 12, 2018 - Low-salt diet may be more beneficial for females than males
December 12, 2018 - Major soil organic matter compound battles chronic wasting disease
December 12, 2018 - Findings may open up new ways to treat dwarfism and other ER-stress-related conditions
December 12, 2018 - New computational model provides clearer picture of shape-changing cells’ structure and mechanics
December 12, 2018 - 10 Facts on Patient Safety
December 12, 2018 - Poorest dying nearly 10 years younger than the rich in ‘deeply worrying’ trend for UK
December 12, 2018 - Innovative care model for children with ASD reduces use of behavioral drugs in ED
December 12, 2018 - Spending time in and around Hong Kong’s waters linked to better health and wellbeing
December 12, 2018 - Simple measures to prevent weight gain over Christmas
December 12, 2018 - Research advances offer hope for patient-tailored AML treatment
December 12, 2018 - Researchers discover a ‘blind spot’ in atomic force microscopy
December 12, 2018 - Sprayable gel could help prevent recurrences of cancer after surgery
December 12, 2018 - SLU researchers explore how fetal exposure to inflammation can alter immunity in newborns
December 12, 2018 - How do patients want to discuss symptoms with clinicians?
December 12, 2018 - Zinc chelation may be able to deliver drug to insulin-producing cells
December 12, 2018 - Brigham researchers develop automated, low-cost tool to predict a woman’s ovulation
December 12, 2018 - Some people with Type 2 diabetes may be testing their blood sugar more often than needed
December 12, 2018 - Slow-growing type of glioma may be vulnerable to immunotherapy, suggests study
December 12, 2018 - Study provides new information regarding microRNA function in cellular homeostasis of zebrafish
December 12, 2018 - Study provides new understanding of mysterious ‘hereditary swelling’
December 12, 2018 - Researchers shed new light on how to combat Shiga and ricin toxins
December 12, 2018 - Pregnant Women Commonly Refuse Vaccines
December 12, 2018 - Drug treatment could offer new hope for some patients with brain bleeding
December 12, 2018 - Health care financial burden of animal-related injuries is growing, study says
December 12, 2018 - Macrophage cells could help repair the heart following a heart attack, study finds
December 12, 2018 - Researchers develop new system for efficiently producing human norovirus
December 12, 2018 - New artificial intelligence-based system to differentiate between different types of cancer cells
December 11, 2018 - Brazilian professors propose guidelines for therapeutic use of melatonin
December 11, 2018 - Healthy Lifestyle Lowers Odds of Breast Cancer’s Return
December 11, 2018 - New research identifies two genes linked to serious congenital heart condition
December 11, 2018 - NIH Director talks science, STEM careers with preteens
December 11, 2018 - Disabling a Cellular Antivirus System Could Improve Gene Therapy
December 11, 2018 - New tool swiftly provides accurate measure of patients’ cognitive difficulties
December 11, 2018 - NICE releases new guidelines for diagnosis and management of COPD
December 11, 2018 - Without Obamacare penalty, think it’ll be nice to drop your plan? Better think twice
December 11, 2018 - Researchers capture high-resolution X-ray and NMR image of key immune regulator
December 11, 2018 - Natural flavonoid is effective at treating leishmanisis infections, study shows
December 11, 2018 - Avoidant grievers unconsciously monitor and block mind-wandering contents, study shows
December 11, 2018 - Study identifies how hantaviruses infect lung cells
December 11, 2018 - Improving PTSD care through genetics
December 11, 2018 - Dermatology providers show interest in recommending cannabinoids to patients
December 11, 2018 - Researchers to study effects of electroconvulsive therapy on Alzheimer’s patients with aggression
December 11, 2018 - Four dried fruits have lower glycemic index than starchy foods, study finds
December 11, 2018 - Optimization of drug dose sizes can reduce pharmaceutical wastage
December 11, 2018 - Ultrarestrictive opioid prescribing strategy linked with reduction in number of pills dispensed
December 11, 2018 - PET scans to optimize tuberculosis meningitis treatments and personalize care, study finds
December 11, 2018 - Researchers aim to identify and target high blood pressure indicators
December 11, 2018 - Researchers identify immune cell subset that may drive chronic inflammation
December 11, 2018 - Ezogabine treatment reduces motor neuron excitability in ALS patients, study shows
December 11, 2018 - One implant, two prices. It depends on who’s paying.
December 11, 2018 - Standardizing feeding practices improves growth trends for micro-preemies
December 11, 2018 - COPD Tied to Obesity in Male, Female Never-Smokers
December 11, 2018 - Flossing: Information for Caregivers
December 11, 2018 - Does breastfeeding hormone protect against type 2 diabetes?
December 11, 2018 - Educating future doctors to prescribe physical activity for their patients
December 11, 2018 - Krystal 2000 microplate design improves fluorescence and luminescence measurement
December 11, 2018 - FDA clears mobile medical app to help increase retention in recovery program for opioid use disorder
December 11, 2018 - Overcoming Challenges in High-Speed Centrifugation Experiments
December 11, 2018 - Study shows link between neighborhoods’ socioeconomic status and dietary choices
December 11, 2018 - Lower BMI before obesity surgery predicts greater post-operative weight loss, study finds
December 11, 2018 - Obesity May Be Driving Rise in Uterine Cancers
December 11, 2018 - Antioxidants may prevent cognitive impairment in diabetes
December 11, 2018 - Study discovers link between meditation and how individuals respond to feedback
December 11, 2018 - Researchers identify potential diagnostic tool for Alzheimer’s disease
December 11, 2018 - Oral cancer prognostic signature identified
December 11, 2018 - How Can I Find Out What Caused My Miscarriage?
December 11, 2018 - Novel personalized medicine tool for assessing inherited colorectal cancer syndrome risk developed
December 11, 2018 - Study uncovers 11 new genes associated with epilepsy
December 11, 2018 - Filling research gaps could help develop more disability-inclusive workplaces
December 11, 2018 - Cartilage tissue engineering brings good news for patients with cartilage defects
December 11, 2018 - Novel 3D printing workflow helps predict leaky heart valves
December 11, 2018 - Imagination can help overcome fear and anxiety-related disorders, shows study
December 11, 2018 - Are caries linked to political regime?
December 11, 2018 - Leader in Diabetes Clinical Trials Wins Naomi Berrie Award
Researchers identify enzyme as potential new drug target for blood disorders

Researchers identify enzyme as potential new drug target for blood disorders

image_pdfDownload PDFimage_print

CHOP, Penn Researchers: CRISPR Screening Reveals Signaling Protein with Key Role in Regulating Hemoglobin in Red Blood Cells

Medical researchers have identified a key signaling protein that regulates hemoglobin production in red blood cells, offering a possible target for a future innovative drug to treat sickle cell disease (SCD). Experiments in cultured human cells reveal that blocking the protein reduces the characteristic sickling that distorts the shape of red blood cells and gives the disease its name.

“We have found a protein with activity specifically in red blood cells that could be a ‘druggable’ target, possibly with a small molecule-;a pill that patients could take to treat sickle cell disease,” said study co-leader Gerd A. Blobel, MD, PhD, a scientist at Children’s Hospital of Philadelphia (CHOP). Blobel and study co-leader Junwei Shi, PhD, of the Perelman School of Medicine at the University of Pennsylvania, published their findings online July 19 in Science.

The signaling protein, or kinase, called HRI, has been known to regulate production of hemoglobin, the iron-carrying component of red blood cells. The new results reveal an unexpected role of HRI in a process called “hemoglobin switching.” This is a transition that normally occurs in newborns during which red blood cells switch from producing a fetal form of hemoglobin to an adult form. The mutation that causes SCD is present in the adult form of hemoglobin, which is why the disease affects patients only after birth.

The SCD mutation causes cells to assume the abnormal crescent shape that clogs blood vessels and damages organs, with painful, sometimes life-threatening results. Hematologists have long known that SCD patients with higher ratios of fetal hemoglobin compared to adult hemoglobin have a milder form of the disease. The drug hydroxyurea, which increases fetal hemoglobin, is the current standard of care, but is not effective in all patients. Therefore, the current researchers sought an improved treatment.

Blobel and Shi relied on a screening tool using CRISPR gene-editing techniques. Shi had previously developed this tool to hone in on specific functional domains of genes, without interfering with the functions of entire genes. In this particular screen, the researchers focused on a class of domains encompassing protein kinases, enzymes that can potentially be inhibited by a small molecule.

The screen enabled the researchers to discover HRI as the kinase that helps to silence fetal hemoglobin production in adult red blood cells. Moreover, by identifying an HRI-regulated transcription factor already known to repress fetal hemoglobin, their study added a piece to the puzzle as to how HRI suppresses fetal hemoglobin production. When they selectively knocked out HRI’s function, they raised the level of fetal hemoglobin in red blood cells.

Crucially, the researchers were able to decrease sickling in red blood cells obtained from SCD patients, without impairing the viability or maturation of the cells-;suggesting that losing the function of HRI is well tolerated.

In proof-of-concept experiments, Blobel and Shi further examined whether a future drug that inhibits HRI might be more effective when combined with other drugs designed to raise fetal hemoglobin. The scientists combined HRI depletion with treatment with pomalidomide, an experimental drug known to increase fetal hemoglobin. In cell cultures, using HRI depletion and pomalidomide together had a stronger effect than using each approach separately, supporting the idea of a combination therapy for SCD.

Another potential application of this finding, added Blobel, may be in another inherited blood disorder, beta-thalassemia, also involving abnormal hemoglobin. Although beta-thalassemias can be caused by many different mutations, a subset of beta-thalassemia patients might benefit from future treatments that target HRI.

“Our long-term goal is to carry out follow-up studies to evaluate whether this approach improves clinical outcomes in patients,” said Blobel. “At this point, our results suggest that HRI is a potential target for a new treatment for disorders of hemoglobin.”

Tagged with:

About author

Related Articles