Immunity and Fibrosis Platform – Pilot Grants

Title: Developing a new mouse model of cancer

Investigative team: Andrew D. Badley, M.D., Richard J. Bram, M.D., Ph.D.

Central hypothesis: Cancer cells express a uniquely modified protein, TRAIL-short, which blocks the induction of death when the cells are treated with TRAIL. A genetically modified mouse will be created that expresses TRAIL-short at high levels, which is predicted to enhance the development and progression of cancers in mice.

Potential outcomes and advances: The creation of this new mouse model will improve the understanding of the role of TRAIL-short in promoting the survival of cancer cells, which can then be used to develop new therapies to block the function of this protein.

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Title: Developing a new technique to predict kidney allograft rejection

Investigative team: Patrick G. Dean, M.D., Joseph P. Grande, M.D., Ph.D., Haidong Dong, M.D., Ph.D.

Central hypothesis: It is not currently possible to predict which patients will reject donor kidneys after transplantation. Identification of early changes to transplant kidneys that precede episodes of rejection will lead to earlier intervention and better outcomes. The investigators hypothesize that a specialized type of macrophage invades the transplanted kidneys early in the rejection process, before the patients become ill, and will examine this hypothesis in a retrospective blinded study.

Potential outcomes and advances: If specialized types of macrophages are found to enter the kidney prior to rejection, screening for these cells could initiate therapies early to save transplant organs and save lives.

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Title: Boosting the immune response to cancer

Investigator: Diana Gil Pages, Ph.D.

Central hypothesis: The use of checkpoint inhibitors to boost the immune response has demonstrated the power of harnessing the patient's own immune system to fight cancer. The investigator hypothesizes that another mechanism of boosting the patient's immune response to cancer is to use a unique reagent to directly prime the patient's T cells. This reagent does not directly activate the T cells, but helps T cells that recognize the cancer work better.

Potential outcomes and advances: The reagent being studied could work alone or in synergy with current checkpoint inhibitors to increase the patient's own immune response to eradicate cancers.

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Title: Disruptions to the blood-brain barrier in autoimmune disease

Investigative team: Charles L. Howe, Ph.D., Debabrata (Dev) Mukhopadhyay, Ph.D., Claudia F. Lucchinetti, M.D.

Central hypothesis: Neuromyelitis optica is an autoimmune disease that disrupts vision and motor function due to the abnormal production of antibodies to one's self (autoantibodies) by the immune system. The investigators hypothesize that these autoantibodies lead to an inflammatory response that disrupts the normal function of the blood-brain barrier.

Potential outcomes and advances: Identification of factors that lead to disruption of the blood-brain barrier could lead to novel therapeutic interventions to restore neural function in neuromyelitis optica.

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Title: Generating antibody-producing B cells

Investigator: Kay L. Medina, Ph.D.

Central hypothesis: Within the immune system, B cells have a unique role to produce antibodies. Defects in B cell production leads to immunodeficiency and increases susceptibility to infections. The investigator has found a novel regulator of B cell generation in the bone marrow, and will develop a new mouse model to test regulation and the ability to increase B cell generation.

Potential outcomes and advances: Boosting B cell production can help fight infections. Therefore, developing new ways to increase the generation of these cells may help patients when their immune systems have been compromised, such as after bone marrow transplant or chemotherapy.

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Title: Designing new vaccinations to fight cancer

Investigative team: Larry R. Pease, Ph.D., Michael A. Barry, Ph.D.

Central hypothesis: The healthy immune system functions to fight foreign invaders but does not target one's own cells. Cancer is unique in that it is a modified "self" that the immune system recognizes poorly. The goal of this project is to design novel strategies to boost the immune response through vaccinations to proteins that contain slight changes from what the immune system recognizes as normal.

Potential outcomes and advances: Cancer vaccines are a new way to fight cancer through the body's own immune system, and the goal of this research is to develop vaccines to boost the immune response to cancer.

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Title: A designer peptide to enhance protective mechanisms against inflammation and fibrosis

Investigative team: John C. Burnett Jr., M.D., Georges Mer, Ph.D., Daniel J. McCormick, Ph.D., Alessia Buglioni, M.D., Valentina Cannone, M.D., Shuchong Pan, Ph.D., Brenda K. Huntley, S. Jeson Sangaralingham, M.S., Ph.D.

Central hypothesis: There is a high, unmet need for drugs to prevent and reverse fibrosis. A novel guanylyl cyclase A receptor (GC-A) activating peptide, MANP, has been designed with robust anti-inflammatory and anti-fibrotic actions. Structure studies on MANP are proposed to enhance its interaction with GC-A and activation of cyclic guanosine monophosphate (cGMP).

Potential outcomes and advances: Critical knowledge gained from this investigation will promote drug optimization and the creation of best-in-class therapeutics based on GC-A.

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Title: Stem cell therapies to prevent vascular restenosis

Investigative team: Sanjay Misra, M.D., Debabrata (Dev) Mukhopadhyay, Ph.D., Edward B. Leof, Ph.D., Andre J. van Wijnen, Ph.D., Allan B. Dietz, Ph.D.

Central hypothesis: While arteriovenous fistulas (AVFs) are the preferred type of vascular access for hemodialysis vascular access, 40 percent of patients with AVFs will develop an abnormal narrowing (stenosis) at the outflow vein within one year. Because mesenchymal stem cells can exert anti-inflammatory and anti-fibrotic effects when transplanted in the outermost layer of the wall (adventitia) of the outflow vein, the investigative team proposes using whole-genome sequencing to identify candidate genes to reduce venous stenosis formation.

Potential outcomes and advances: The investigation will provide a mechanistic understanding of how stem cell therapies can be used to prevent stenosis in AVF placement.

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Title: A mouse model to study and alleviate asthma

Investigative Team: Christina M. Pabelick, M.D., Jordan D. Miller, Ph.D.

Central hypothesis: Caveolin-1 is thought to play an important role in the pathophysiology of several diseases, including pulmonary fibrosis and pulmonary and systemic hypertension. Because global knockout of caveolin-1 results in multiorgan failure life span reduction, the investigators propose that a conditional smooth muscle-specific caveolin-1 knockout mouse will promote a critical understanding of the in vivo importance of caveolin-1 in the pathogenesis of airway diseases such as asthma.

Potential outcomes and advances: The proposed mouse model will provide scientists with a new tool to understand the contribution of caveolin-1 signaling to inflammation, airway hyperactivity and remodeling.

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Title: Noninvasive imaging and detection of liver fibrosis

Investigative team: Vijay Shah, M.D., Daniel J. Tschumperlin, Ph.D., Richard L. Ehman, M.D., Edward B. Leof, Ph.D.

Central hypothesis: It is proposed that genome-scale differences in RNA expression profiles can be identified to understand the mechanistic basis by which increases in tissue stiffness reflect organ fibrosis detectable by magnetic resonance elastography (MRE).

Potential outcomes and advances: This investigation will identify novel targets to be evaluated in established animal models of liver injury and fibrosis. The eventual goal is to use MRE imaging technology more effectively as a noninvasive diagnostic tool for fibrosis of the liver and other organs.

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