Goal 3: Advance Translational Research

Direct Upregulation of Antioxidant Defenses as a Therapeutic Strategy

Clinical trials involving administration of antioxidants such as vitamin C or vitamin E as therapeutic strategies for cardiovascular diseases associated with oxidant stress have proven to be surprisingly disappointing. A particularly attractive alternative approach is direct upregulation of endogenous antioxidant defenses such as NRF2 via dietary approaches. NRF2 is a master antioxidant and cell protective transcription ...more »

Submitted by (@jlombard)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Direct upregulation of endogenous antioxidant defenses such as NRF2 via dietary approaches will avoid the well known caveats of drug-based approaches such as off target effects and detrimental side effects. Dietary supplements such as Protandim are already available; and beneficial effects of other NRF2 up-regulators such as resveratrol and sulforaphane are beginning to be recognized. The dietary approach is minimally invasive and has high preventative value.

Feasibility and challenges of addressing this CQ or CC :

Addressing this CQ is clearly feasible, as dietary supplements are currently available for humans, and the beneficial effects of foods containing compounds that upregulate the NRF2 system, e.g., broccoli, cauliflower, red wine, and grape juice are currently recognized. One challenge in addressing this question in animal models to date is that the only genetic model lacking NRF2 is a knockout mouse model, which have substantial limitations for in vivo physiological studies due to their small size. However, a recent R21 grant (#1R21OD018309-J. H. Lombard, P.I.) has allowed the development of a NRF2 knockout rat model which is better suited for physiological studies than the mouse model. In addition, the techniques used to develop the NRF2 knockout rat can be applied to multiple disease-sensitized strains, e.g., the Dahl salt-sensitive rat. Fawn Hooded Hypertensive rat, Obese Zucker rat, etc. Similar disease sensitized rodent genetic strains are not available in mice.

Name of idea submitter and other team members who worked on this idea : Julian H. Lombard

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Goal 2: Reduce Human Disease

Can transcutaneous carboxyhemoglobin measure endogenous heme oxygenase activity?

Non-invasive measurement of transcutaneous carboxyhemoglobin (SpCO) by CO-oximetry has been shown to reflect disease activity in asthma, allergic rhinitis, Staphylococcal pneumonia/sepsis and to correlate positively with lung function in cystic fibrosis. Given published studies of heme oxygenase activity in these diseases as a reflection of oxidant or inflammatory activity, does measurement of SpCO reflect endogenous ...more »

Submitted by (@lekurlandsky)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Laboratory measurement of heme oxygenase activity in inflammatory and states of oxidative activity in multiple disease states, lung diseases for instance, has become important in measuring disease severity and activity as well as being an indicator of disease modification by gene polymorphisms of heme oxygenase. The simple measurement of transcutaneous carboxyhemoglobin if correlated with heme oxygenase activity would provide a ready assessment for clinicians in the clinical setting.

Feasibility and challenges of addressing this CQ or CC :

In a setting in which heme oxygenase activity is measured and clinical patients of varying diseases are available, this question could be answered reasonably easily without technical difficulty.

Name of idea submitter and other team members who worked on this idea : Lawrence E. Kurlandsky, MD

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