Rock Creek Pharmaceuticals Inc. (fka RCPIQ)

[Buddhahead]

Chronic Inflammation and Age-related Disease (R01), Funding Opportunity Announcement (FOA) Number: PAR-13-233 Funding Application by Department of Health and Human Services, Posting date: May 30, 2013, Start submission date: September 5, 2013, Expiration date: September 8, 2014

FUNDING OPPORTUNITY PURPOSE:
"The participating NIH Institutes and Centers invite applications to address both the origins and the effects of low level chronic inflammation in the onset and progression of age-related diseases and conditions. Chronic inflammation, as defined by elevated levels of both local and systemic cytokines and other pro-inflammatory factors, is a hallmark of aging in virtually all higher animals including humans and is recognized as a major risk factor for developing age-associated diseases. The spectra of phenotypes capable of generating low-level chronic inflammation and their defining mediators are not clear. Further, a clear understanding of how chronic inflammation compromises the integrity of cells or tissues leading to disease progression is lacking. The role of dietary supplements and/or nutritional status in chronic inflammation in age-related disease is also poorly studied. Thus, there is a critical need to establish the knowledge base that will allow a better understanding of the complex interplay between inflammation and age-related diseases. Applications submitted to this FOA should aim to clarify the molecular and cellular basis for the increase in circulating inflammatory factors with aging, and/or shed light on the cause-effect relationship between inflammation and disease, using pre-clinical (animal or cellular based) models."

"Background
A central molecular feature of acute inflammation is the production, primarily by innate immune cells, of cytokines, chemokines, and other inflammatory molecules that often expand the response from its tissue of origin to a systemic level. There is considerable epidemiological evidence indicating that aging is associated with a chronic increase in circulating levels of several of these same effectors, including IL-6, TNF-alpha and CRP. The age-related increase in circulating levels of these mediators is generally several orders of magnitude lower than that observed during the classical acute inflammation that occurs in response to injury or infection. In contrast, however, it is significantly longer in duration, often measured in years rather than hours.

Chronic inflammation has been linked to major age-related changes including physical frailty, energy imbalance, homeostatic dysregulation, and changes in body composition which in turn are believed to underlie many of the chronic diseases and conditions affecting the elderly. Indeed, chronic inflammation has been linked to many age-related chronic diseases including neurodegeneration, Alzheimer’s disease, atherosclerosis, cancer, sarcopenia, kidney and lung diseases, metabolic syndrome, diabetes and many others.

Several critical questions remain unanswered, including the cellular origin of the inflammatory mediators and their role in age-related disease, either as causative agents or as a consequence of tissue damage, or whether both are interconnected by a more complex linkage. The role of dietary supplements and/or nutritional status on chronic inflammation is also of interest but poorly studied. It has been proposed that poor immune function, persistent infections (e.g., by CMV or HIV), and breakdown of the intestinal barrier during aging could lead to chronic activation of the innate immune system. In addition, research has shown that pro-inflammatory cytokines can be produced both by senescent cells present in many tissues (and often in higher abundance at sites of injury) and by pre-adipocytes present in fat depots, which also tend to increase with age. At the sub-cellular level, several potential drivers should be examined, including the NF-kB pathway, free radicals, or autophagy. The degree to which each cell type contributes to chronic inflammation at different sites and in relation to different chronic diseases is another open question. Similarly, the role of inflammatory mediators might vary with each specific chronic disease and this also needs to be addressed.

Perhaps the most critical need is to fully understand the potential effects, both positive and negative, of blocking the inflammatory state on different age-related diseases and conditions. While there is epidemiological evidence suggesting a causative role for chronic inflammation in age-associated disease onset and progression, the evidence is still inconclusive. Several clinical trials are currently in progress that will address whether reducing the inflammatory state can affect outcomes (cardiovascular, diabetes and others) in individuals with otherwise comparable classical risk factors for those diseases, yet even the necessary basic understanding of the biology behind these approaches is incomplete.

Purpose
This FOA aims to clarify the molecular and cellular basis for the increase in circulating inflammatory factors with aging, and to shed light on the cause-effect relationship between inflammation and disease, using pre-clinical (animal or cellular-based) models.

Areas of Research Interest
The focus of this FOA is on understanding the basic molecular and cellular mechanisms that link aging with inflammation and chronic diseases. The long term view is to better inform clinical trials and eventually interventions that will directly benefit humankind, but clinical trials are not the focus of this FOA. Experimental approaches might include ablation of relevant aspects of the chronic inflammatory state, comparative biology, expression profiles, or others. Examples of responsive areas of research include, but are not limited to:

Develop novel technologies and/or approaches that increase the ability to measure low level inflammation in the context of aging organisms.
Identification of the origin of the pro-inflammatory state associated with aging.
Further definition of the signature of chronic (as opposed to acute) inflammation in humans or animal models.
Investigations on the role of chronic inflammation in immune-privileged tissues such as the brain.
Studies on the role of inflammation on general conditions of aging (frailty, resilience) that predispose to diseases or conditions.
Studies on the crosstalk between inflammation and tissue metabolic or physiological function.
Identification of feedback loops and cross-talk between disease and inflammation.
Possible trade-offs involved in approaches that diminish or eliminate the pro-inflammatory state of aging.
In animal models, testing the effect of anti-inflammatory interventions on the development of age-related diseases and conditions.
In addition to these common areas of interests, the participating Institutes and Centers (ICs) are interested in the following areas of research:

Office of Dietary Supplements (ODS):

Studies on the role of dietary supplements and/or nutritional status in the chronic inflammation and age related diseases.

National Institute on Alcohol Abuse and Alcoholism (NIAAA):

Many diseases associated with chronic alcohol consumption overlap with those associated with aging, including neurodegeneration, lung infection, muscle wasting, cardiovascular diseases, diabetes, and some cancers. Chronic alcohol consumption leads to chronic elevation of inflammatory markers in circulation. Therefore, NIAAA proposes the following topic areas:

Characterization of inflammatory mediator profiles associated with aging in the presence and absence of chronic alcohol consumption and expansion of this profile to include more specific and stable markers in the general population. Examination of the relationship between aging and excessive alcohol on chronic inflammatory markers and whether these effects are additive or synergistic would be of interest.
Investigations on the cellular origin of the inflammatory mediators in age-related inflammation, compared and contrasted with alcohol-related inflammation.
Comparisons between mechanisms associated with the increased susceptibility to pneumonia due to aging or as a consequence of chronic alcohol intake.
The role of subclinical inflammation and oxidative stress in muscle wasting and comparisons between age-related vs alcohol-related sarcopenia.

National Institute of Allergy and Infectious Diseases (NIAID):

Studies to understand the links between age-related adiposity, low-level chronic inflammation, and immune system dysfunction in the elderly.
Mechanisms by which incomplete resolution of an immune response to infection contributes to age-related chronic inflammation.
Effects of increased levels of reactive oxygen species, declines in anti-oxidant capacity, and/or activation of the innate immune response on age-associated chronic inflammation.
Determine the mechanisms by which chronic inflammation contributes to immune system dysfunction associated with aging, such as poor immune responses to infections and/or vaccines, and increased incidence of immune-mediated disease.
Identification of mechanisms or pathways that could be targeted to prevent or reverse chronic immune activation in HIV-infected individuals on suppressive antiretroviral therapy.
National Institute of Environmental Health Science (NIEHS):

Studies that identify the role of environmental exposures in initiating and/or sustaining a chronic inflammatory state.
Studies that focus on genetic susceptibility to chronic inflammation and its interaction with environmental exposure in determining risk or protection from age-related diseases or disorders.
National Center for Complementary and Alternative Medicine (NCCAM):

Studies to elucidate molecular targets using non-nutritional natural products that likely modulate the effects of inflammation-induced pain in the elderly. With NCCAM has a special interest in projects that address the following program areas:

Natural product modulators of inflammation-induced pain that elucidate novel mechanisms of action, including analgesic or noxious stimuli (plant derived analgesics, marine neurotoxins, venoms).
Anti-inflammatory properties of probiotics in immunosenescence and pain in the elderly.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS):

The role of chronic inflammation in the pathophysiology, etiology and progression of diseases or conditions in the NIAMS mission area, including (and not limited to) osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, psoriasis, alopecia areata, wound healing. (NIAMS webpage/long range plan: http://www.niams.nih.gov/About_Us/Mission_and_Purpose/long_range.asp)

National Institute of Child Health and Human Development (NICHD):

NICHD is interested in how the inflammatory cytokines generated by adipocytes and by macrophages embedded in the fat mass as a result of childhood obesity can accelerate the appearance of diseases associated with aging, especially T2DM, now commonly seen in adolescence, and atherosclerotic plaques in the third decade.

National Heart, Lung, and Blood Institute (NHLBI):

Investigation into the influence of chronic inflammation associated with aging on the development, etiology and progression of diseases within the NHLBI mission, including (and not limited to) hypertension, aneurysm, lymphatic disease, peripheral vascular disease, atherothrombosis, coronary artery disease, heart failure, idiopathic pulmonary fibrosis (IPF), asthma, chronic obstructive pulmonary disease (COPD), lung vascular disease, anemia, venous thromboembolism (VTE), and chronic inflammatory complications as a function of age that develop in patients following blood transfusion or hematopoietic stem cell transplantation (HSCT), or with hemoglobinopathies.

National Cancer Institute (NCI):

Studies that define mechanistically how aging-associated inflammation causes cancer initiation, progression, or affects the tumor microenvironment.
Studies that identify or characterize how etiological factors such as viruses, the microbiota, or chemical exposures influence inflammation-mediated tumorigenesis in aging individuals or models."

Application Guide/Instructions at:
http://grants.nih.gov/grants/guide/pa-files/PAR-13-233.html