Goal 2: Reduce Human Disease

Bringing Personalized Biochemistry and Biophysics to Bear on Problems of Personalized Heart, Lung and Blood Medicine

Precision medicine will provide unprecedented opportunities to tailor health care based on knowledge of personal patterns of genetic variations. These variations usually impact protein or RNA sequences, resulting in altered properties. These alterations can result in increased susceptibility to a particular disease or intolerance to common therapeutics. To take full advantage of knowing a patient’s set of gene variations, ...more »

Submitted by (@chuck.sanders)

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

Details on the impact of addressing this CQ or CC :

As detailed in the attached review (Kroncke et al. Biochemistry 2015, 54, 2551−2559) the successful practice of personalized medicine will in many cases require a molecular-level understanding of the nature of the defects that are caused by disease-predisposing genetic variations. As widespread personal genome sequencing becomes routine, numerous genetic variations (many millions) of uncertain significance will be discovered. Using both experimental and computational tools associated with the fields of biochemistry, biophysics, and structural biology it is in many cases possible to ascertain whether a newly-discovered gene variation adversely impacts a critical protein or RNA function and, if so, how. Among various clinical applications this information can be used (i) to project whether a patient not currently showing symptoms for a particular disease is likely to present with that disease in the future (sometimes enabling prophylactic therapy), (ii) to help establish the molecular etiology of a disease currently afflicting the patient, and (iii) to guide the therapeutic strategy pursued for that patient.

Feasibility and challenges of addressing this CQ or CC :

My lab is already participating in a project (RO1 HL122010) with two other labs (those of Drs. Jens Meiler--Vanderbilt and Alfred George--Northwestern) to develop personalized biochemical and biophysical approaches for application to genetic variations impacting the KCNQ1 gene, potentially predisposing patients to long QT syndrome, a cardiac arrhythmia. However, our project deals with one gene and one disorder only. There clearly is a need for improved and expanded communication and collaboration between those practicing personalized/precision medicine and those who are well-equipped to provide medically actionable molecular insight using the approaches of personalized biochemistry, biophysics, and structural biology.

Name of idea submitter and other team members who worked on this idea : Charles R. Sanders, Prof. of Biochemistry, Vanderbilt University (With Drs. Alfred George--Northwestern University and Jens Meiler--Vanderbilt University)

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Goal 2: Reduce Human Disease

Defining the developmental abnormalities leading to birth defects

Can we define the developmental abnormalities leading to birth defects and extrapolate that knowledge to define strategies for regeneration?

 

How can we recognize initiation of disease earlier?

Submitted by (@nhlbiforumadministrator)

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

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 1: Promote Human Health

Use of Evolutioinary Biology in Medicine

Given that chronic diseases are 'Evolutionary Biology' in reverse, can we use developmental and phylogenetic principles to diagnose and treat them safely and effectively?

Submitted by (@johntorday)

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

Details on the impact of addressing this CQ or CC :

Biomedical research is currently in crisis. Both basic science and translational science are failing to provide new insights to the causes of disease and their eradication. Instead, we are encouraged as biomedical researchers to devise ways of eliminating the symptoms of disease. This is a very bad practice since it facilitates the retention of maladaptive genes in the gene pool.

 

This practice is the result of continuing to practice biology and medicine descriptively, like Chemistry and Physics were as Alchemy and Astrology. The lack of a fundamental understanding of the First Principles of Biology originating in unicellular organisms fosters continued study of associations and correlations instead of causal mechanisms. If the National Science Foundation were still funding Astrology, we would see the same lack of predictive value that we see in biology and medicine today. Society cannot afford to continue sponsoring such pseudoscience. This problem is already recognized indirectly due to the failure of the Human Genome Project to fulfill its promise of curing common chronic diseases such as heart attack, stroke, diabetes and obesity. But the withholding of funding from the NIH to shake out the dead wood will not solve the problem, because it is due to the use of the wrong paradigm. Understanding how and why vertebrates evolved on the cellular-molecular level offers a way of understanding causation in biology and medicine rendering them predictive.

Feasibility and challenges of addressing this CQ or CC :

This initiative is highly feasible since we already have the methods available to us in the biomedical research community. The problem is in recognizing that applying 'omics' to the problems we face using same old same old Pathophysiology will not solve the problems of medicine. That precept is founded on Health as the absence of disease, which proved useful for a century, but we are now attempting to tackle more difficult fundamental problems that require a more powerful approach. The Evolutionary Biology approach offers the opportunity to define Health objectively rather than relativistically, i.e. health and disease are a continuum generated by the mechanisms of evolution.

Name of idea submitter and other team members who worked on this idea : John Torday, Virender Rehan, Neil Blackstone

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Goal 2: Reduce Human Disease

Vascular biology and the pathophysiology of sepsis

Unravel the cellular & molecular mechanisms related to the vascular biology of sepsis and related cardiovascular collapse. The goal is to develop a new scientific framework for the prevention of sepsis related morbidity and mortality by applying novel approaches to discover new targets for biomarkers and therapy by promoting multidisciplinary research required for scientific cross-talk between complementary research disciplines ...more »

Submitted by (@greg.martin)

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

Name of idea submitter and other team members who worked on this idea : Society of Critical Care Medicine Executive Committee/Council

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Goal 2: Reduce Human Disease

National network to study the pathobiology of sepsis

Sepsis is the leading cause of death in hospitalized patients, the 3rd leading cause of death in all people in the US, the most common condition leading to widespread vascular collapse, among the most common causes of respiratory failure, and a frequent cause of acute cardiac dysfunction.

Submitted by (@greg.martin)

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

Details on the impact of addressing this CQ or CC :

Developing a national network to address important aspects of sepsis (causes and consequences of cardiac dysfunction, molecular determinants of respiratory failure) and serve as a trials group for testing novel interventions for new discoveries.

Name of idea submitter and other team members who worked on this idea : Society of Critical Care Medicine Executive Committee/Council

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Goal 2: Reduce Human Disease

Redox regulation of cardiovascular and lung disease through thiols

Redox imbalance as represented by alterations in oxidative versus reductive stresses are well appreciated to occur during nearly all forms of cardiovascular and lung diseases. However, specific molecular mechanisms responsible for these changes remain largely unknown and poorly organized. Study of redox biology principals has revealed that protein cysteine thiols are a unique target for redox posttranslational modifications ...more »

Submitted by (@ckevil)

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

Details on the impact of addressing this CQ or CC :

Protein cysteine thiols are recognized to be important for multiple signaling and cell biology functions due to unique properties of oxidation/reduction resulting in a 'thiol switch'. However, oxidative modifications of thiols are highly complex involving nitrosation, sulfhydration, sulfenylation, and glutathiolyation among many others. It has become increasingly clear that these posttranslational modifications are associated with cardiovascular and pulmonary pathophysiology. Yet, many important questions remain such as: how these thiol modifications occur during disease and differ from health? How do these thiol switches impact protein function involved in cellular pathophysiology? And can thiol switch manipulation be exploited for therapeutic purposes to maintain cellular and organ health or treat disease? In order to begin to answer these questions, careful and comprehensive investigations are required to understand thiol-switching principals employing a host of molecular, biochemical and pathophysiological approaches.

Feasibility and challenges of addressing this CQ or CC :

Given the significant advances in quantitative analytical chemical and molecular techniques, molecular redox mediators and pathways, non-invasive imagine modalities and comprehensive translational study designs; multiple fields are uniquely poised that could provide significant insight into this critical challenge. Primary objectives would be to establish consensus analytical methodologies, chemical and molecular biology approaches, and cellular and animal models in conjunction with rigorous clinical investigations. Results from efforts at understanding the importance of ‘thiol switches’ will make significant clinical impact on cardiovascular and lung pathogenesis and would feasibly be accomplished in 5-10 years.

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Goal 1: Promote Human Health

Intersecting Developmental Biology with Vascular Physiology and Biology

Although many think of the vasculature as a lump sum of vessels that all react in a similar fashion to a certain stimulus, e.g., alpha-adrenergic activation, this is not the situation. For example, coronary resistance vessels show little to no direct response to alpha-adrenergic activation while resistance vessels in most organs show marked constriction. Another example is the response of different vessels to angioplasty ...more »

Submitted by (@wchilian)

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

Details on the impact of addressing this CQ or CC :

A challenge facing many specialists in vascular medicine, vascular surgery, and cardiology is understanding the ramifications, and the basis, of the vascular pathology in the context of the organ system. Another way of re-stating this as a question is: Are the unique attributes of the vascular biology, pathology and physiology of a particular organ system connected to specific aspects of development. This question would help both the basic on clinical scientists understand the basis of why a blood vessel in the kidney may be different than one in the heart, or in the brain with the goal of devising more selective therapies to approach vascular disease in specific organs. Scientists in the area of vascular development have long appreciated that vascular cells in different organs arise from different embryological origins; yet how this information translates into the intricacies of vascular control, or responses to pathology is not resolved. Understanding the basic biological mechanisms of how the embryological source of the vasculature affects pathology and physiology could engender treatment of vascular disorders.

Feasibility and challenges of addressing this CQ or CC :

This idea could be implemented by encouraging multi-PI efforts from vascular developmental biologists, and investigators engaged in studies of microvascular control mechanisms and/or vascular biologists interested in vascular pathologies such as restenosis and vascular lesions. Advances in fate mapping techniques have enabled developmental biologists to track embryological origins of cells into specific organ systems into adulthood. With such a multi-faceted approach a better understanding of vascular physiology and pathophysiology will be obtained that hopefully will be translated into more effective treatments.

Name of idea submitter and other team members who worked on this idea : William M. Chilian

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Goal 2: Reduce Human Disease

How to maximize the opportunities and promise of emerging omics research? Develop scientific commons

In the late 20th century, the NHLBI cohorts were created as separate entities with specific research goals. The NHLBI’s funding of GWAS served as a powerful incentive for collaboration among the NHLBI-funded cohort studies. The creation of a scientific commons would provide a major national resource comprising the participants, their deeply phenotyped data, their biological samples, and the investigator expertise to ...more »

Submitted by (@psaty0)

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

Details on the impact of addressing this CQ or CC :

Advance discovery and treatment

Feasibility and challenges of addressing this CQ or CC :

Feasible with few challenges. The system would need infrastructure support.

Name of idea submitter and other team members who worked on this idea : Psaty & Tracy

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Goal 4: Develop Workforce and Resources

Training approaches in lymphatic biology

The lymphatic vascular network connects the parenchymal interstitium through the nodes to the veins. Lymph serves as the transport pathway between these compartments and via its flow, controls interstitial fluid, macromolecular exchange, lipid absorption, immune cell trafficking and is critical to edema prevention/resolution, lipid metabolism, inflammation and immunity. Knowledge of this vascular network lags far behind ...more »

Submitted by (@dcz000)

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

Details on the impact of addressing this CQ or CC :

NIH has acknowledged that the lack of training in the field of lymphatic biology has impaired research progress in the area. Traditional methods that the NIH uses (T32) have not adequately addressed this issue as there are currently NO such programs in existence. One of the critical problems that must be overcome to advance the field is that few individual institutions in the US have a large enough body of lymphatic biology investigators to fit the classic training grant schemes. Overcoming this hurdle will significantly help advance research in the field. Consideration of other innovative approaches that utilize web-based or other methods to deliver distance education among local or regional institutions in this field should be investigated. Establishment of these innovative approaches would broaden the pool of investigators for research training and would significantly advance the field and thus be of high impact.

Feasibility and challenges of addressing this CQ or CC :

Research in the lymphatic biology field has historically lagged behind other vascular areas. However, interest in lymphatic biology and medicine has grown rapidly over the last decade. The Lymphatic Education & Research Network (formerly LRF) has had a long-standing commitment to developing research and training in lymphatic biology through its post-doctoral fellowship program, support for conferences/symposia and by providing travel funds for early-stage investigators to attend these meetings. Since very few places in the US have enough researchers trained and active in lymphatic biology, initiatives to broaden the base for research training would have to utilize novel approaches. Thus, the challenge will be to develop training programs that can address the needs of new lymphatic biologists at multiple institutions at geographically distributed sites. Approaches that use modern communication IT technology, and distance learning methods could deliver parts of the training. But innovative approaches to incorporate training beyond didactic learning need to be developed.

Name of idea submitter and other team members who worked on this idea : D. Zawieja

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Goal 1: Promote Human Health

Host and environmental factors effect on transplantation biology and regenerative medicine

How does inflammation and cell injury induce the immune system during transplant rejection? How do we control immune responses to enable cell- and tissue-regenerative strategies? • How does inflammation and cell injury induce the immune system during transplant rejection? • How do we control immune responses to enable cell and tissue regenerative strategies? • How do we use iPS cell based and gene editing based therapies ...more »

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

Treatment of human diseases

Feasibility and challenges of addressing this CQ or CC :

Facilitated by progress in genome editing, stem cell biology, immunology

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 2: Reduce Human Disease

Novel methods to diagnose and treat microvascular ischemia

Microvascular ischemia is common, particularly in the setting of critical illness. We need better ways to evaluate, diagnose and treat these conditions, whether they relate to microvascular myocardial ischemia, as a primary diagnosis of complication of other acute illness, or non-myocardial ischemia during the course of surgery, injury, infection or acute illness.

Submitted by (@greg.martin)

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

Details on the impact of addressing this CQ or CC :

Development of effective diagnostics would lead to improved treatments for myocardial and non-myocardial microvascular ischemia, and also advance understanding to extend the advance beyond this setting.

Name of idea submitter and other team members who worked on this idea : Society of Critical Care Medicine Executive Committee/Council

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