UMDF will once again host “The Big Pitch” where four post-doc researchers who are selected out of 50+ applicants, compete for a $50,000 accelerators prize. Each finalist gives a five-minute pitch on their research project live at the conference.
UMDF accelerators have the exclusive opportunity to vote for their favorite pitch. Visit the UMDF accelerators page or drop by a UMDF booth to find out how to become an accelerator today.
Washington University in St. Louis
Therapeutic degrader molecules targeting excessive mitophagy in FBXL4- and PPTC7- associated Mitochondrial Disease
Mitochondria are commonly known as the “Powerhouses” of our cells, generating a large amount of the energy needed by our cells and bodies. In functioning as these cellular powerhouses, mitochondria can become damaged over time, and this damage can spread to other parts of the cell if not corrected. Therefore, cells have evolved ways to remove these damaged mitochondria to limit their accumulation in a process called “mitophagy”. One challenge for cells is being able to distinguish damaged from healthy mitochondria to ensure that only bad mitochondria are targeted for removal. If healthy mitochondria are accidentally labeled for removal, this can decrease the number of mitochondria in cells and, in some cases, causes Mitochondrial Disease. We recently discovered that cells have at least two proteins which act as superheroes (their science names are FBXL4 and PPTC7) to stop these removal signals and save healthy mitochondria. When these superhero proteins no longer do their jobs, cells remove mitochondria unnecessarily, even though they are healthy and functional. This means that patients are not able to produce enough energy to function and grow because they don’t have enough mitochondria. The good news is that our recent work has identified key information about the superhero proteins: we recently discovered how they mute the removal signals and preserve healthy mitochondria. In this project, we will use this knowledge to design a molecule that mimics these superhero proteins to mute the removal signals to save mitochondria. This molecule could, in principle, correct the accumulation of these removal signals, and could be used to preserve healthy mitochondrial populations in select Mitochondrial Diseases. The concept behind this treatment that is already in clinical trials as a cancer therapeutic, so we are hopeful that, if this project is successful, we may be able to translate it to treat a subset of Mitochondrial Diseases that currently have no cure.
Children’s Medical Center Research Institute
at University of Texas Southwestern
Diagnosing and monitoring mitochondrial disease non-invasively with deuterium metabolic imaging
Mitochondrial diseases, which interfere with how our cells make energy, are among the most common genetic disorders. They are difficult to diagnose, because there are hundreds of individual mitochondrial diseases and most cause nonspecific symptoms such as muscle weakness, seizures, and intellectual disability. A long-standing challenge is that we cannot directly assess mitochondrial function in the organs most commonly affected (e.g. brain and muscle) without a biopsy. Deuterium metabolic imaging (DMI) is a new approach that could solve this problem. Deuterium is a heavy form of hydrogen used to label nutrients like glucose (sugar). Tissues take up labelled glucose and pass the deuterium to other molecules through cellular metabolism, much of which occurs in the mitochondria. Therefore, the abundance of labelled metabolites reflects the amount of mitochondrial activity. Magnetic resonance is used to detect deuterium-containing molecules, similar to the way MRI reports the structure of internal organs. We will use mice with mitochondrial diseases affecting the brain or muscle. Deuterium-labeled nutrients will be injected through a vein, and MRI will be used to measure the appearance of deuterium-labeled molecules in the brain and muscle. We predict that mitochondrial disease will reduce the level of these labelled molecules, and this will allow us to “diagnose” mitochondrial disease in mice. Importantly, DMI has already been used in humans, although not yet in mitochondrial diseases. Completing these studies will pave the way to use DMI in human mitochondrial diseases, for diagnostic purposes and to test whether new treatments improve mitochondrial function.
Northumbria University
Monoclonal antibody therapy for Leigh Syndrome
Mitochondria, also known as the powerhouse of the cells, are critical for energy production to keep an organism healthy. However, genetic mutations can affect these structures causing their impaired function and leading to serious diseases affecting the brain and muscles. Leigh syndrome (LS) is a severe childhood brain disorder causing movement problems, seizures, and breathing difficulties, often leading to early death and there is currently no cure. Inflammation, including immune cells called monocytes and macrophages, has been discovered to play a key role in worsening LS. Blocking these immune cells, can, therefore, reduce pathology symptoms but some treatments are toxic. This project will explore safer treatments by using antibodies to remove these immune cells and prevent pathology in a mouse model of LS. This research could lead to better therapies for children with LS and other mitochondrial diseases.
The Scripps Research Institute
Pharmacologic Activation of the Integrated Stress Response to Ameliorate Mitochondrial Dysfunctions Associated with Imbalances in Mitochondrial Proteostasis
Most of the energy requirements of the cell are fulfilled by tiny organelles called mitochondria. The mitochondria have special enzymes called proteases inside them to help clear out damaged proteins and maintain its health and functionality. When these proteases lose its ability to function, due to genetic mutations, it can lead to serious diseases like dominant optic atrophy (DOA), spastic ataxia (SPAX), CODAS, and Leigh syndrome. Unfortunately, there are currently no available drugs that can correct the mitochondrial dysfunctions which are associated with these diseases. However, our cells do have a natural defense mechanism called the Integrated Stress Response (ISR). The ISR comprises of four different proteins – PERK, GCN2, PKR and HRI – that trigger a downstream chain of events through which the cells adjust its metabolism and help the mitochondria adapt and recover under normal conditions of stress. I hypothesized that activating this pathway will help correct the mitochondrial dysfunctions linked to these diseases even when their proteases are not working properly. I am using advanced screening techniques to identify small molecule drugs that will gently activate the ISR. By doing this, I aim to show that boosting the ISR could help cells better cope with the mitochondrial problems caused by defective proteases.
