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Genetic and Metabolic Disease Program

Much of the human genome is dedicated to regulating metabolic pathways in cells and tissues. Therefore, many human diseases involve metabolic defects that arise from mutations and that prevent tissues from carrying out their physiological functions. Scientists in CRI’s Genetic and Metabolic Disease Program (GMDP) are identifying the genetic basis of new human diseases and uncovering the mechanisms that link metabolic anomalies to tissue dysfunction. Understanding these mechanisms will lead to better treatments for diseases that involve perturbed metabolism.
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Our Approach to Genetic and Metabolic Diseases

Work in the following areas allows CRI researchers to uncover connections between mutations, metabolic dysfunction, and disease.

On average, the genetic makeup of any two people differs by 1 in every 1,000 base pairs, totaling more than 3,000,000 genetic differences per genome. This incredible amount of genetic variation accounts for much of the phenotypic diversity we observe in humans, including phenotypes related to disease. We use sequencing to identify disease-causing genetic variants in patients, then use experimental models to understand how these variants cause disease and how to restore health.
Inborn errors of metabolism (IEMs) are a large category of rare human diseases caused by mutations in metabolic enzymes and nutrient transporters. We integrate metabolomics (i.e., chemical composition of the blood) with advanced sequencing technologies to understand how human metabolism is regulated, determine why some mutations give rise to disease, and discover new, potentially treatable IEMs.

Metabolism is regulated by a vast array of intracellular and extracellular cues. These cues activate or repress signaling and gene expression pathways that profoundly impact cell state and, ultimately, health. We are interested in how cells sense and respond to nutrients, oxygen, and metabolic waste products and how these processes go awry in disease.

Many of the mutations that cause cancer arise in genes that regulate metabolism. These mutations reprogram how cells acquire nutrients and convert those nutrients into energy and building blocks. Some reprogrammed pathways impose vulnerabilities that can be therapeutically targeted to treat cancer. CRI is a world leader in discovering mechanisms of metabolic reprogramming in cancer and identifying metabolic pathways that promote cancer progression.

Embryonic development requires a precisely orchestrated series of events that govern the timely emergence of distinct populations of cells with specialized characteristics and functions. Metabolic dysfunction can interfere with this process, impairing organ development. We are studying how metabolic anomalies in utero alter embryonic development and cause disease.

The GMDP performs clinical research to understand, diagnose, and treat genetic and metabolic diseases. In IEMs, through partnerships with the Division of Pediatric Genetics and Metabolism at UT Southwestern and clinical collaborators from around the world, we use genomics and metabolomics to identify disease-causing mutations and understand how these mutations impact the metabolic state. We then use data from these studies to tailor therapies in patients and define disease risk within families. In cancer, we pioneered techniques to probe tumor metabolism directly in patients, providing an entirely new way to discover metabolic pathways that drive cancer progression. We are using data from these studies to develop better treatments for cancer.

GMDP Faculty

Gerta Hoxhaj, Ph.D.

Discovered new mechanisms by which mammalian cells regulate compartment-specific redox metabolism.

Shang Ma, Ph.D.

Identified mutations that connect altered sensation of mechanical stimuli to diseases in the blood and musculoskeletal system.

Sam McBrayer, Ph.D.

Created mouse and human-derived models of brain tumors and used them to discover targetable metabolic vulnerabilities.

Prashant Mishra, M.D., Ph.D.

Defined the consequences of genetically-defined mitochondrial defects on tissue function, regeneration, and metabolism.

Hijai Regina Shin, Ph.D.

Defined new mechanisms by which cells sense cholesterol and signal its abundance to mTORC1, the master regulator of cell growth.

Affiliated Research Faculty

Affiliated Clinical Faculty

Featured GMDP Discoveries

Metabolism
November 2024

Mishra Lab discovers mitochondrial DNA mutations prevent metastasis in skin cancers

Mishra Lab: Human cells contain DNA in two places — the nucleus and mitochondrion — and mutations in mitochondrial DNA (mtDNA) prevent cancer cells from entering the bloodstream and halt the spread of skin cancer. Researchers discovered that while mtDNA mutations did not prevent a tumor from growing, the mutations stopped cancer cells from invading into the blood stream and spreading to other organs. Science Advances 10:eadk8801
Cancer Biology, Metabolism
July 2024

Tumor growth fueled by nucleotide salvage

Hoxhaj lab: Cancer cells salvage purine nucleotides to fuel tumor growth, including purines in foods we eat, an important discovery with implications for cancer therapies. CRI researchers challenged the long-standing belief that tumors primarily acquire purine nucleotides – building blocks for DNA, which is required for cellular growth and function – by constructing them from scratch via de novo synthesis. Research also shows tumors significantly use the more efficient salvage, or recycling, pathway to acquire purines. Cell 187, 3602-18
Metabolism, Regenerative Medicine
June 2024

Metabolic inflexibility keeps damage at bay during liver regeneration

Mishra lab: Researchers identified a type of metabolic inflexibility during liver regeneration that prevents cells with dysfunctional mitochondria from proliferating, which demonstrates one way regenerative cells root out damage. When their mitochondria are damaged, hepatocytes turn on PDK4, a metabolic enzyme that stops the cells from shifting to an alternative source of acetyl-CoA, so they can’t proliferate. Science 384:eadj4301
Cancer Biology, Genetics
August 2022

Researchers identify new druggable therapeutic pathway in a deadly form of brain cancer

McBrayer lab: Discovered that mutations in IDH genes, which are common in adult and adolescent brain tumors, cause cells to become addicted to a metabolic process called de novo pyrimidine nucleotide synthesis. This addiction stems from the ability of IDH mutations to increase susceptibility to DNA damage, which provides new insights into the ways that these mutations reprogram brain cell biology. Cancer Cell 40, 939-956
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