Tim Huang Archives - Sanford Burnham Prebys

Tag: Tim Huang

Institute News

Investigating individual immune responses to COVID-19 vaccination and infection

AuthorGreg Calhoun
Date

March 3, 2025

mRNA concept stock image

New study analyzes how the set of proteins in blood plasma changes following vaccination and infection, and may contribute to improving vaccine development

While many people have received similar mRNA vaccinations to protect against COVID-19, the strength and duration of the resulting immunity varies. It remains unclear exactly what causes individuals’ immune systems to react differently to the COVID-19 vaccine and other immunizations.

To get a better understanding of this phenomenon, scientists at Sanford Burnham Prebys, Seer Inc. and Federal University of Rio Grande do Sul examined the type and amount of virtually all proteins in the blood plasma of 12 volunteers as they received two doses of the Pfizer-BioNTech mRNA COVID-19 vaccine. The research team published the results of this pilot study in the Journal of Proteome Research on February 4, 2025, detailing the first attempt to comprehensively explore how an mRNA vaccine changes the mix and concentration levels of proteins known as the proteome.

The scientists were able to study a set of more than 3,000 proteins, within which they found a set of proteins that changed following each dose of vaccine. The authors also found a set of proteins that could distinguish between research participants who had or had not tested positive for COVID-19 in the months after receiving the second dose of vaccine.

While more research is needed with larger groups of research volunteers, this pilot study suggests that studying proteome changes can increase our understanding of how individuals’ immune systems react differently to immunization. Future findings from additional experiments may reveal methods for developing more effective vaccines.

Svetlana Maurya, PhD

Svetlana Maurya, PhD, is director of the Sanford Burnham Prebys Proteomics Shared Resource.

Lucélia Santi, PhD, professor adjunto at the Federal University of Rio Grande do Sul, is the senior and corresponding author on the study.

Ting Huang, PhD, a scientist at Seer Inc. focused on data science and machine learning, is first author on the manuscript.

Additional authors include:

  • Alex Rosa Campos, Ramón Díaz and Svetlana Maurya, from Sanford Burnham Prebys
  • Jian Wang, Alexey Stukalov, Khatereh Motamedchaboki, Daniel Hornburg and Serafim Batzoglou, from Seer Inc.
  • Laura R. Saciloto-de-Oliveira, Camila Innocente-Alves, Yohana P. Calegari-Alves and Walter O. Beys-da-Silva, from Federal University of Rio Grande do Sul
Institute News

New insights into Alzheimer’s disease

AuthorMonica May
Date

September 25, 2020

Long neurites growing from neurons with extra SORLA

Sanford Burnham Prebys scientist publishes two papers that bring us one step closer to understanding—and potentially treating—the devastating condition.

For millions of families and caregivers around the world, the need for an effective treatment for Alzheimer’s disease remains urgent despite the ongoing pandemic. Now, two studies from Timothy Huang, PhD, who was recently promoted to assistant professor in the Degenerative Diseases Program at Sanford Burnham Prebys, bring us one step closer to understanding the root cause of the disease.

Brain protein may help protect against Alzheimer’s disease  

Previous research from Huang and his colleagues showed that a neuronal protein called SORLA helps reduce production of toxic amyloid beta protein that accumulates and leads to Alzheimer’s disease. Given this important role, Huang decided to dig deeper to understand SORLA’s “job” inside the brain.

In a paper featured on the cover of The Journal of Neuroscience, Huang and his team analyzed mice that produce high levels of SORLA and studied the effects of enhancing SORLA on the brain. This work showed that higher levels of SORLA resulted in elongated neurites, structures that extend from neurons, and improved the repair and regeneration of axons—the cable-like fibers that neurons use to communicate. These findings suggest that drugs that increase levels of SORLA might help protect the brain against Alzheimer’s disease and may even help people with a spinal cord injury. 

Huang describes the findings as “the tip of the iceberg” and is eager to learn more about this important protein—with the ultimate goal of identifying potential targets for drugs that could slow the progression of Alzheimer’s disease. 

A new model for studying Alzheimer’s disease 

Many of the mutations associated with Alzheimer’s disease are found in a brain cell type called microglia. However, unlike other cells, mouse microglia are very different from human microglia. Because scientists primarily use mouse models to understand disease, this difference limits their ability to understand how microglial mutations lead to Alzheimer’s disease.  

To overcome this hurdle, Huang and his team took on the formidable task of creating human stem cell lines that contain Alzheimer’s mutations found in human microglia. The scientists then tracked the downstream effects of these mutations in the cells, including epigenetic and gene expression changes, which revealed many new, previously unknown relationships between Alzheimer’s-associated genes. The findings were published in the Journal of Experimental Medicine. 

More studies are needed to fully understand the how these interactions alter the course of Alzheimer’s disease—which can now be answered using this new model. Huang, who describes the work as “one of the most challenging and ambitious projects I’ve worked on so far” believes the cell line may also be used to help screen for potential Alzheimer’s disease drugs. 
 

Institute News

Attacking Alzheimer’s disease by controlling toxic proteins

AuthorBill Stallcup, PhD
Date

August 25, 2017

Alzheimer's disease - neurons with amyloid plaques shutterstock_111506315

The formation of amyloid-b plaques (aggregates of the amyloid-b protein) in the brain is one of the hallmarks of Alzheimer’s disease, a pathological disorder in which the death of neurons leads to dementia. Although the details involved in this process are still highly debated, many researchers agree that excessive levels of amyloid b protein (Ab for short) lie at the root of the disease. Accordingly, much research is currently focused on determining the cause of Ab build-up.

Huaxi Xu, PhD, professor and Jeanne & Gary Herberger Leadership Chair in Neuroscience at SBP, explains that, “Ab is a fragment derived from a larger protein called amyloid precursor protein (APP). The toxic Ab fragment is produced by the action of enzymes that operate inside the cell. In contrast, the action of enzymes that operate outside the cell produce a different set of non-toxic fragments of APP that are part of a normal APP recycling/replenishment system on the neuron cell surface. We wondered if we could minimize the toxic cleavage events that occur inside the cell by promoting the non-pathological, cell surface recycling of APP.”

In a recent report in the Journal of Neuroscience, the flagship journal of Society for Neuroscience, the Xu lab identified candidate molecules that might be important for promoting the cell surface recycling of APP. According to post-doctoral associate Timothy Huang, PhD, first author on the paper, “Loss of a recycling protein called SORLA has been observed in Alzheimer’s patients. Our experiments show that SORLA forms a complex with an intracellular navigational protein, SNX27, which can redirect SORLA and its binding target APP to the cell surface. On the surface, APP mostly undergoes non-pathological processing rather than generating Ab.”

Further validation of this inside versus outside concept was achieved by tweaking cellular levels of SORLA and SNX27 in cultured neurons. Increasing the levels of SORLA and SNX27 resulted in higher levels of APP on the cell surface, thus avoiding production of the toxic Ab fragment. In contrast, decreasing the levels of SORLA and SNX27 kept APP largely inside the cell, thus increasing its vulnerability to pathological cleavage.

Xu emphasizes that future work will need to aim at determining whether these SORLA-SNX27-APP interactions can be exploited in mouse models of Alzheimer’s as a means of preventing or lessening the effects of the disease.

Institute News

New potential way to slow advance of Alzheimer’s

AuthorJessica Moore
Date

July 27, 2016

Silver-stained brain tissue showing senile plaque

Like weeds taking over a garden, the brains of Alzheimer’s patients become congested with clumps of protein. These clumps arise when a peptide called amyloid beta takes a shape that sticks to other amyloid beta molecules and converts them to the same sticky form, causing a chain reaction. The sticky form of amyloid beta is toxic, so as amyloid plaques accumulate, neuronal connections, and eventually whole neurons, are lost.

Research from the laboratory of Huaxi Xu, PhD, professor in the Degenerative Diseases Program, suggests a new possible way to minimize the generation of amyloid beta and slow the advance of this tragic disease. Alzheimer’s, which affects more than 5 million people and is the 6th leading cause of death in the US, destroys patients’ memory and, at later stages, their ability to communicate and understand their surroundings.

“Our results could eventually help us discover therapeutics that address the progression of Alzheimer’s disease,” said Xu. “That would be a big step forward—no such treatment has yet been approved.”

In the new study, published in the Journal of Neuroscience, Timothy Huang, PhD, a postdoc in Xu’s lab, examined the function of a receptor called SORLA because variants of the gene encoding it had been linked to early-onset Alzheimer’s. SORLA had also been shown to affect trafficking—transport from one cellular compartment to another—of amyloid beta’s precursor. Amyloid beta is generated only in acidic compartments, where the precursor is cut to yield the toxic form, so trafficking has a big impact on how much amyloid beta is made.

“We found that SORLA, with its partner SNX27, moves the amyloid precursor protein away from the acidic compartment, where it would be cut into amyloid beta, to the cell surface,” said Huang. “There, the amyloid precursor protein is cut in a way where it cannot be cut into amyloid beta.”

“Modulating trafficking of the amyloid precursor protein through SORLA could be a new way to treat Alzheimer’s,” added Xu. “Other strategies of decreasing levels of amyloid beta, such as inhibiting the enzyme that cuts the precursor, have failed in the clinic, so new approaches are needed.”

Xu and Huang next plan to investigate whether enhancing amyloid precursor trafficking via SORLA reduces loss of neurons and improves cognitive function in an animal model of Alzheimer’s.

The paper is available online here.