Prioritising research funding focuses research efforts on the root causes of CFS and avoids wasting money on researching secondary symptoms and "pet projects" which have little or no value. Prioritising research funding imposes discipline, integrity and structure on the research process, and this can save valuable time, money and resources, and achieve faster and better results which will lead to a diagnostic tool for CFS and successful treatments.

We need more national government funding for research which investigates the root causes of CFS and how they are related to the various abnormalities and dysfunctions found in CFS. The following research areas are in order of importance and funding priority:

1. Genetic factors in CFS. 
   Chart the changes in gene expression in CFS. In 2005, scientific researchers found abnormalities in 16 genes (Journal of Clinical Pathology, 2005 ; 58: 826-832). The following genes were abnormally expressed
   ABCD4, PRKCL1, MRPL23, CD2BP2, GSN, NTE, POLR2G, PEX16, EIF2B4, EIF4G1, ANAPC11, PDCD2, KHSRP, BRMS1, and GABARAPL1, IL-10RA.
   Click here for full research paper.  
   Further research and studies will reveal other gene abnormalities in CFS. The following areas would be vitally important : 

   -	The genetic reasons for the RnaseL abnormality and accompanying STAT1-alpha and p53 deficiencies and how all of this contributes to immune system dysfunction and other abnormalities found in CFS.
   -	Genetic reasons for increased  neutrophil  apoptosis, over-activation of the TH2 cytokines, and under-activation of TH1 cytokines, altered interferon production, low NK cell numbers and activity, weakened cell mediated immunity.
   -	Genetic reasons for the mitochondria dysfunction found in CFS
   -	The genetic effects of infection by specific viruses and / or mycoplasmas  and  exposure to certain toxins and heavy metals found in CFS patients

   Can these processes be blocked and / or can the pathways be restored to normal by gene based therapies ?  ;

    

2. RnaseL abnormality
   The reasons for the following:
   (i) the cleavage of the 80 kDa form of RnaseL into 37 kDa RnaseL. The accompanying high  LMW RnaseL (37 kDa)  to  HMW RnaseL (80 kDa) ratios found in CFS patients
   (ii) the cleavage of STAT1-alpha protein, and accompanying STAT1-alpha deficiencies
   (iii) the cleavage of p53 protein, and accompanying p53 deficiencies
   (iv) the abnormal caspase activity and disrupted cell apoptic process
   (v) The cleavage of RnaseL leads to  the presence of RnaseL fragments. 3 RnaseL fragments have been found to be significant: 
   Fragment 1, an ankyrin binding repeat domain which is known to interact with various transport proteins. It is is capable of NF-kappaB mimicry ; 
   Fragment 2,  the 2-5A binding fragment that has catalytic activity and thus is able to degrade RNA ; 
   Fragment 3, shares homology with chain A of Cdk6 (Cyclin dependent kinase). It  of Cdk6 chain A mimicry ;
   Research article:   Total Exposure: Expanded Model for RNase L Fragmentation in CFS Uncovered; The National CFIDS Foundation Announces the Use of Elastase Inhibitors as a Potential Treatment for CFS Patients (2003)
   (vi) Cell Apoptosis (cell death) increases initially in CFS and then is inhibited when the levels of Rnase L related fragments reach a certain point
   (vii) cleavage of Actin ;
   
   All of the above factors (i) to (vii) above interfere with the 2-5A synthetase / RNaseL pathway which is part of the anti-viral and anti-mycoplasma defense mechanism in cells. RnaseL destroys both viral messenger RNA and human messenger RNA. An over-active RnaseL destroys human messenger RNA preventing synthesis of essential human proteins and putting cells into significant dysfunction. Research by Suhadolnik, De Meirleir  and De Becker show that the abnormal RnaseL in CFS is over ten times as destructive as normal Rnase L, and this destructive phase continues indefinitely for years.
   
   What is causing all of these abnormalities and how is it doing it ? The chief suspects are: 
   - human luekocyte elastase (tests carried out by Dr. Kenny De Meirleir seem to confirm that elastase is the main culprit)
   - calpain 
   - protease
   - other proteolytic enzymes
   - ATP deficiency and abnormal mitochondria degeneration and destruction
   - environmental chemicals and toxins
   - mercury poisoning
   - other heavy metals
   - ciguatera poisoning
   - prolonged and excessive release of stress hormones. Part played by Adrenal gland burn-out, HPA axis dysfunction.
   - specific viruses: HHV6a virus, EBV, CMV, Stealth virus (from a subclass of retroviruses called "spumaviruses"), JHK virus,  Parvovirus B-19, Enteroviruses mainly Cocksackie B in spinal fluids, blood, brain, nerve tissue and muscle tissues:
   - specific mycoplasmas: M. fermentans, M. penumoniae, M. hominis, M. penetrans, M. pirum,  M. incognito. 
   - chlamydia: chlamydia pneumonia
   - does one of the above infections initiate an immune response which somehow leads to the cleavage of the 80 kDa form of RnaseL into 37 kDa RnaseL, the cleavage of STAT1-alpha protein, etc. and the beginning of CFS.
   
   Each of the above factors must be analysed in some depth in order to determine their part in the cleavage of the 80 kDa form of RnaseL and  the cleavage of STAT1-alpha protein, the abnormal caspase activity, the STAT1-alpha and p53 deficiencies, etc.
   
   Can this process be blocked and / or can the pathways be restored to normal ?
   Why is the drug Ampligen effective in many cases, and why is long-term treatment necessary ?
   
   

3. Effects of Rnase L (37 kDa RnaseL) :
   RnaseL destroys both viral messenger RNA and human messenger RNA. An over-active RnaseL destroys human messenger RNA preventing protein synthesis within cells and putting cells into significant dysfunction. Research by Suhadolnik, De Meirleir and De Becker show that the abnormal Rnase L (37 kDa RnaseL) in CFS is over ten times as destructive as normal Rnase L, and this destructive phase continues indefinitely for years. 
   What are the full effects of LMW RnaseL (37 kDa RnaseL) and RnaseL fragments on:
   - human messenger RNA
   - protein synthesis within cells and other cell functions  
   - mitochondria function & ATP production. Does it contribute to the abnormally high build-up of lactic acid in the cells of CFS patients ?
   - the liver
   - the immune system
   - the kidneys
   - growth hormone production
   - HPA glands
   - muscles
   - brain and nervous system
   
   How is the RnaseL abnormality and accompanying STAT1-alpha and p53 deficiencies related to other immune system dysfunctions such as 
   - suppression of TH1 cytokines and over-activation of TH2 cytokines
   - increased  neutrophil apoptosis
   - altered interferon production
   - low natural killer cell numbers and activity levels
   - weakened cell mediated immunity ? 
   Can this process be blocked and / or can the pathways be restored to normal ? ;

   According to Dr. Paul Cheney (who has successfully treated hundreds of CFS patients) the above effects form Phase I of CFS ; this can last from a few months to a few years.
   Can this process be blocked and / or can the pathways be restored to normal ? ;
   
   

4. Elastase is involved in CFS,  it can inflict the following : 

   -	cleaves insulin-like growth factors and their binding proteins. It induces a significant proteolytic cleavage of IGFBP-3 ? Why is the IGFBP-3 / IGF-1  ratio greater than 3.5 in many CFS patients ? Why is this leading to low growth hormone levels ?
   -	the cleavage of the 80 kDa form of RnaseL into 37 kDa RnaseL  (tests carried out by Dr. Kenny De Meirleir seem to confirm this)
   -	cleaves T4-binding globulin, adversely affecting thyroid hormones
   -	cleaves corticosteroid binding globulins, adversely affecting corticosteroids and adrenal hormones
   -	elastase regulates Stromal cell-derived factor-1 (SDF-1) / CXCR4 binding. This is very significant because Human Herpes Virus-6 (HHV-6) uses the CXCR4 receptor for infection. HHV-6 virus infection has been found in a majority of CFS patients
   -	cleavage of Actin. This has also been found in Behcet's disease.
   -	Elastase is also involved in chronic inflammation, and several inflammatory diseases

   Most of the above factors are involved in CFS. What are the full effects of elastase in CFS  -  immune system effects, hormone effects, HPA axis effects, neurological effects, liver effects, mitochondria effects ? Can it explain the wide variety of dysfunctions and abnormalities found in CFS ?
   What starts or brings about this destructive elastase activity ?
   Can this elastase activity be blocked and / or can the pathways be restored to normal ? ;
   
   

5. According to Dr. Paul Cheney (who has successfully treated hundreds of CFS patients) LMW RnaseL by destroying messenger RNA and blocking protein synthesis disrupts the production of liver enzymes and leads to impaired Liver detoxification. This leads on to a build-up of toxicity in the body which forms Phase II of CFS. This increased level of toxicity damages the brain and several organs and glands, worsening the effects of CFS. This can last from two years to ten years or more. 

   -	What are the full effects of LMW RnaseL ( 37 kDa RnaseL)  and RnaseL fragments on liver functions and detoxification in CFS patients ?
   -	Do CFS patients have impaired Liver detoxification and a build-up of toxicity in the body and if so, what is causing it ? Is this related to the depletion / deficiency of growth hormone and Glutathione found in most CFS patients ?
   -	Why is there a urinary marker called CFSUM 1 in CFS and how is it related to intestinal infection and toxicity ?

   Can these processes be blocked and / or can the pathways be restored to normal ? ;
   
   

6. According to Dr. Paul Cheney (who has successfully treated hundreds of CFS patients) the build-up of toxicity in the body becomes cumulative over time, damaging the brain, mainly the subcortex in the brain, the hypothalamus, the pituitary gland and adrenal gland, the immune system, muscles, cell functions, mitochondria & ATP production, and nervous system. This ongoing damage has a particularly devastating effect on CFS patients, causing severe fatigue. Thus patients remain in a state of sickness over many years. This forms Phase III of CFS ; this can last from three to twenty years or more. This toxicity leaves people highly susceptible to premature deaths from cancers, opportunistic infections and heart attacks.
   What are the full effects of this toxic build-up on the following :

   -	Hypothalamus, the pituitary gland and adrenal gland. Identify structural and functional defects, and hormonal deficiencies. Concentrate firstly on the lack of growth hormone, cortisol and anti-diuretic hormone, which are the main hormonal deficiencies found in CFS patients.
   -	Subcortex in the brain
   -	Mitochondria & ATP production. Including the abnormally high build-up of lactic acid in the  cells of CFS patients.
   -	Glutathione levels in the body
   -	Immune system function

   Does this build-up of toxicity play a part in the progression and worsening of CFS ?  
   Can this process be blocked and / or can the pathways be restored to normal ? ;

    

7. Mitochondria :
   Scientists have consistently found abnormal mitochondria degeneration and destruction in CFS patients (see Scientific Evidence section ). What is causing this ?
   Why is there defective mitochondria function in CFS patients ? Why are the mitochondria not completing the aerobic processes that metabolise glucose, to form complete oxidation ?  Why is there an abnormally high build-up of lactic acid in the cells of CFS patients ? Scientists already know that if mitochondria can't function properly, pyruvate is converted to lactate acid and other organic acids. Does this explain the intracellular acidosis and extracellular alkalosis found in CFS ?
   What exactly is causing this mitochondria dysfunction ?
   -  LMW RnaseL (37 kDa RnaseL)
   -  STAT1-alpha and p53 deficiencies
   -  Lack of human messenger RNA
   -  Lack of protein synthesis
   -  Deficiency of SOD and / or Glutathione. This would force the body to cut back on or shut down the aerobic energy conversion process.
   -  Glutathione reduction induces an increase in citrate levels, which can inhibit 2,3 DPG. Citrate is a very potent inhibitor of 2,3 DPG in the red cells. A deficiency of 2,3 DPG leads to a reduction of oxygen to the mitochondria.
   -  Alkaline blood (Alkaline blood inhibits oxygen transport to the mitochondria)
   -  Mercury poisoning. Mercury can interfere with and block Glutathione.
   -  The build-up of  toxins and heavy metals within the body
   -  Viral and / or mycoplasma infection
   -  DNA Gene Re-arrangement or Alterations in Normal Expression
   -  Growth Hormone Deficiency
   
   Can this process be blocked and / or can the pathways be restored to normal ? ;
   
   

8. Why is there Chronic Ciguatera poisoning in a majority of CFS patients ? ;
   Can this disease process be blocked and / or can the pathways be restored to normal ? ;
   
   

9. Brain :  
   - Reasons for brain hypo-perfusion and lesions
   - Reasons for dysfunction of the subcortex
   - Reasons for cortisol and serotonin abnormalities
   - Why is there excess NMDA activity in the brain and a deficiency of GABA activity ?
   
   Can this disease process be blocked and / or can the pathways be restored to normal ? ;
   
   

10. The full effects of the following infections in the spinal fluids, blood, brain, nerve tissue and muscle tissues of CFS patients:
    specific viruses: HHV6a virus, EBV, CMV, Stealth virus (from a subclass of retroviruses called "spumaviruses"), JHK virus,  Parvovirus B-19, Enteroviruses mainly Cocksackie B.
    specific mycoplasmas: M. fermentans, M. penumoniae, M. hominis, M. penetrans, M. pirum,  M. incognito. 
    chlamydia: chlamydia pneumonia  
    
    

11. Are the crimson crescents in the mouth related to an ongoing viral infection ? Is it a form of Kasposi's Sarcoma ?
    
    

12. Why is there a unique urinary marker called N-methylpyrrolidine found in a significant number of CFS patients ? This is associated with  amyloid formation and protein misfolding, is this part of CFS ? The expression of the Huntington's protein in CFS patients,  using gene expression analysis at the CDC points towards amyloid formation and a neuro-degenerative process in CFS.
    Is this related to the RnaseL abnormality, STAT1-alpha and p53 deficiency or to elastase activity or to Chronic Ciguatera poisoning ?
    Can this disease process be blocked and / or can the pathways be restored to normal ?   
    
    

13. The interactions between all of the above abnormalities ;

If there is a lack of CFS researchers or technological resources within a country then the national government should sub-contract out research to top researchers in other countries who will be able to carry out the research work and deliver the results.