Grants, Honors, Awards & Recognitions

A new study from the lab of Michael Lodato, PhD, published in Nature, sheds light on the molecular changes that occur in the human brain during the normal aging process at an extraordinary level of detail.

For the study, the Lodato lab obtained brain samples (specifically, prefrontal cortex) from 19 human donors, ranging in age from 0.4 to 104 years, from the National Institutes of Health NeuroBioBank repository. Using a trifecta of single-cell analysis technologies—single-nucleus RNA-sequencing, single-cell whole genome sequencing, and spatial transcriptomics—they generated a comprehensive catalog of age-related, cell-type specific changes in the transcriptomic and genomic landscape, creating an unprecedented map of the transformations that occur in the human brain across the lifespan.

The study identified cell clusters specifically in the infant brain that are enriched for the expression of neurodevelopmental genes, consistent with the idea that brain development continues after birth. They also found, unexpectedly, that expression of neuron-specific genes remains unchanged throughout life. However, they observed widespread downregulation of certain housekeeping genes during aging, with short, highly expressed housekeeping genes exhibiting high mutation rates, suggesting that a combination of gene length, gene function, and genome damage shapes the transcriptome of the aging brain.

Read the full article in Nature.

MCCB researcher Junhao Mao, PhD, and his collaborator Thomas Carroll, PhD, Director of Basic Science Research in Nephrology at University of Texas Southwestern Medical Center, have received a joint grant from the US Department of Defense Kidney Cancer Research Program to further their work on the identification of immunomodulatory targets of TAZ/SRF in sarcomatoid renal cell carcinoma progression.

Sarcomatoid renal cell carcinoma (sRCC) is a rare, aggressive subtype of kidney cancer with generally poor prognosis and limited treatment options. Although the majority of sRCC patients fail to respond to immune checkpoint inhibitor (ICI) therapy, emerging data indicate that a subset of sRCC patients are sensitive to ICIs. Factors that promote immune evasion in sRCC represent potential therapeutic targets whose inhibition may reduce tumor growth or sensitize tumors to immunotherapy. They may also represent much needed biomarkers to accurately predict which patients will respond to ICI therapy.

Using both mouse and human models of sRCC, Drs. Mao and Carroll will explore the mechanistic basis by which the transcription factors TAZ and SRF promote immune evasion, with the goal of identifying direct transcriptional targets of TAZ and SRF involved in tumor progression and immune escape. They will also test whether pharmacological inhibitors of TAZ/SRF activity can block tumor progression and sensitize tumors to ICI therapy.

The results of the study may reveal novel therapeutic targets and biomarkers for sRCC, potentially guiding the development of more effective treatment strategies.

Richard Gregory, PhD, has received a five-year NIH U01 grant from the National Cancer Institute (NCI) to study the role of tRNA modification reprogramming and translational remodeling in cancer. Dr. Gregory leads the collaborative grant, which brings together three other researchers from Beth Israel Deaconess Medical Center (Elena Piskounova, PhD) and Brown University (Juan Alfonzo, PhD, and Sergej Djuranovic, PhD).

The grant was one of just three awarded under NCI’s RNA Modifications Driving Oncogenesis (RNAMoDO) initiative, which aims to “promote fundamental studies in the emerging area of RNA modifications that underlie the oncogenic process, focusing on the central role of RNA modifications in translational reprogramming of cancer cells.”

The project will comprehensively catalog tRNA modifications—and corresponding changes in mRNA translation—during melanoma progression and metastasis, and investigate the role of tRNAs and tRNA-modifying enzymes in stress response pathways, tumorigenesis, and metastasis. The results of the study will provide a deeper understanding of how tRNA modification reprogramming and translational remodeling contribute to cancer development, and may reveal tRNA-modifying enzymes as novel therapeutic targets.

Scot Wolfe, PhD, is part of a multidisciplinary team at UMass Chan, along with Erik Sontheimer, Fen-Biao Gao and Jonathan Watts in the RNA Therapeutics Institute, that has received an NIH grant from the National Institute of Neurological Disorders and Stroke (NINDS) to develop precision editing of granulin mutations that cause frontotemporal dementia.

Frontotemporal dementia (FTD) is the most common form of dementia in people under 60, and currently there is no cure or treatment to slow the progression of the disease. The collaborative grant aims to develop an effective precision genome editing approach to correct mutations in the Granulin (GRN) gene, which account for approximately 20–25% of hereditary FTD cases, or about 10% of total FTD cases. The efficacy of the candidate genome editing approaches will be tested in induced pluripotent stem cell (iPSC)-derived neurons and glial cells, and their effectiveness in preventing disease progression will be assessed using a humanized FTD mouse model.

The research aims to not only lead to an effective treatment strategy for FTD associated with GRN mutations, but also to establish a roadmap for developing clinical genome editing approaches to correct mutations in other genes that cause FTD and other forms of dementia.

Mitochondrial dysfunction and neuroinflammation have been implicated in neurodegenerative diseases, but whether these processes are mechanistically linked, and whether they actively contribute to the pathogenesis of neurodegeneration, has remained uncertain.

New research from the lab of Eric Baehrecke, PhD, bridges this gap by demonstrating how mitochondrial dysfunction can initiate neuroinflammation and trigger neuronal cell death, ultimately contributing to neurodegeneration. The work, led by Guangyan Miao, PhD, a postdoctoral researcher in the Baehrecke lab, was recently published in the journal Nature Structural & Molecular Biology.

Read more about the study and its therapeutic implications. 

Kelsey Wagner, a 5th year graduate student in the lab of Michelle Kelliher, PhD, has received an Emerging Scientist Grant from the private foundation Kids Beating Cancer.

Wagner’s thesis research focuses on elucidating the molecular mechanisms that drive therapy resistance and disease relapse in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive form of leukemia that primarily affects children. Relapse is thought to arise from a rare subpopulation of cells known as leukemia-initiating cells (L-ICs), which are quiescent (dormant) and resistant to chemotherapy, but can later exit quiescence, begin proliferating and re-establish disease.

Recent work from the Kelliher lab identified a gene expression signature in T-ALL mouse-derived L-ICs, which revealed upregulation of Btg2, a gene encoding a protein known to regulate quiescence in T cells through its ability to promote mRNA deadenylation and decay.  Interestingly, BTG2 is downregulated in relapsed T-ALL patients, suggesting decreased BTG2 expression may contribute to disease progression.

In her Emerging Scientist Grant project, Wagner will use RNA-sequencing (RNA-seq) and poly-A tail length sequencing (PAL-seq, done in collaboration with Athma Pai’s lab in the RNA Therapeutics Institute) to comprehensively identify BTG2 target mRNAs. The goal of the research project is to generate a list of validated BTG2 targets that can be further evaluated in mouse xenograft experiments to determine whether their depletion resensitizes therapy-resistant T-ALL patient samples to chemotherapy—thereby uncovering potential targets for therapeutic development.