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1、END OF GRANT REPORTS OUTCOMES OF NHMRC FUNDED RESEARCH INTO DIABETESENDING 2000 TO 2012CONTENTSNote: Each Administering Institution in the Contents list is linked to the Administering Institution in the Summary pages. To go to a Summary page, ctrl click on the name of the Admin Inst in the Contents

2、page. To return to the Contents Page, Ctrl click on the Admin Inst on the Summary Page. This document can also be searched using the Edit Find function (ctrl+f) HYPERLINK l AustinHospitalMedicalResearchFoundat2 Austin Hospital Medical Research Foundation HYPERLINK l AustinResearchInstitute2 Austin R

3、esearch Institute HYPERLINK l AustralianNationalUniversity2 Australian National University HYPERLINK l BakerIDIHeartandDiabetesInstitute2 Baker IDI Heart and Diabetes Institute HYPERLINK l BondUniversity2 Bond University HYPERLINK l CancerCouncilVictoria2 Cancer Council Victoria HYPERLINK l Centrefo

4、rEyeResearchAustraliaLtd2 Centre for Eye Research Australia Ltd HYPERLINK l CSIRODivisionofHumanNutrition2 CSIRO Division of Human Nutrition HYPERLINK l CurtinUniversityofTechnology2 Curtin University of Technology HYPERLINK l DeakinUniversity2 Deakin University HYPERLINK l EdithCowanUniversity2 Edi

5、th Cowan University HYPERLINK l FlindersUniversity2 Flinders University HYPERLINK l GarvanInstituteofMedicalResearch2 Garvan Institute of Medical Research HYPERLINK l HowardFloreyInstitute2 Howard Florey Institute HYPERLINK l InternationalDiabetesInstituteInc2 International Diabetes Institute Inc HY

6、PERLINK l JamesCookUniversity2 James Cook University HYPERLINK l LaTrobeUniversity2 La Trobe University HYPERLINK l MacfarlaneBurnetInstituteforMedical2 Macfarlane Burnet Institute for Medical Research and Public Health HYPERLINK l MenziesResearchInstitute2 Menzies Research Institute HYPERLINK l Men

7、ziesSchoolofHealthResearch2 Menzies School of Health Research HYPERLINK l MonashUniversity2 Monash University HYPERLINK l MurdochChildrensResearchInstitute2 Murdoch Childrens Research Institute HYPERLINK l PrinceHenrysInstituteofMedicalRese2 Prince Henrys Institute of Medical Research HYPERLINK l Qu

8、eenslandInstituteoFMedicalResearch2 Queensland Institute of Medical Research HYPERLINK l QueenslandUniversityoftechnology2 Queensland University of Technology HYPERLINK l RMITUniversity2 RMIT University HYPERLINK l RoyalMelbourneInstituteoftechnology2 Royal Melbourne Institute of Technology HYPERLIN

9、K l RoyalPrinceAlfredHospital2 Royal Prince Alfred Hospital HYPERLINK l StVincentsInstituteofMedicalResear2 St Vincents Institute of Medical Research HYPERLINK l SwinburneUniversityoFTechnology2 Swinburne University of Technology HYPERLINK l SydneyWestAreaHealthService2 Sydney West Area Health Servi

10、ce HYPERLINK l TheDrEdwardKocFoundationLimited2 The Dr Edward Koch Foundation Limited HYPERLINK l UniversityofAdelaide2 University of Adelaide HYPERLINK l UniversityofMelbourne2 University of Melbourne HYPERLINK l UniversityofNewSouthWales2 University of New South Wales HYPERLINK l UniversityofNewca

11、stle2 University of Newcastle HYPERLINK l UniversityofQueensland2 University of Queensland HYPERLINK l UniversityofSouthAustralia2 University of South Australia HYPERLINK l UniversityofSydney2 University of Sydney HYPERLINK l UniversityofTasmania2 University of Tasmania HYPERLINK l UniversityofTechn

12、ologySydney2 University of Technology Sydney HYPERLINK l UniversityofWesternAustralia2 University of Western Australia HYPERLINK l UniversityofWollongong2 University of Wollongong HYPERLINK l VictorChangCardiacResearchInstitute2 Victor Chang Cardiac Research Institute HYPERLINK l VictoriaUniversity2

13、 Victoria University HYPERLINK l WalterandElizaHallInstitute2 Walter and Eliza Hall InstituteGrant ID: 266505Start Year: 2004CIA Name: Prof George JerumsEnd Year: 2006Main RFCD:Nephrology and UrologyTotal funding: $288,900.00Admin Inst: HYPERLINK l AustinHospitalMedicalResearchFoundat Austin Hospita

14、l Medical Research FoundationGrant Type: NHMRC Project GrantsTitle of research award: Normoalbuminuric and albuminuric pathways to renal insufficiency in type 2 diabetesLay Description (from application):Up to one third of patients with type 2 diabetes develop kidney disease (diabetic nephropathy).

15、An increase in protein excretion in the urine (albuminuria) is usually the first sign of kidney disease. Albuminuria usually progresses from normal levels to an intermediate phase (microalbuminuria) lasting 5-10 years and is then followed by overt nephropathy (macroalbuminuria). It has been traditio

16、nally believed that onset of a decline in kidney function, measured as glomerular filtration rate, accompanies the development of diabetic kidney disease. However, recent studies by our group have shown that about one quarter of patients with type 2 diabetes have impaired kidney function without an

17、increase in albuminuria. This raises the possibility that an alternate non-albuminuric pathway leads to kidney disease in a subgroup of patients with type 2 diabetes. This study will compare kidney structure and function in patients with type 2 diabetes and impaired kidney function with or without i

18、ncreases in albuminuria. The comparison will be accompanied by measurements of the rate of decline in kidney function over 5 years or more, in subjects with or without increases in albuminuria in order to confirm that kidney function may decline independently of albuminuria. The demonstration of alt

19、ernate mechanisms of renal injury has the potential to identify new targets for the treatment of kidney disease in patients with type 2 diabetes.Research achievements (from final report):The research that we have performed has highlighted the potential benefits of accurately detecting kidney dysfunc

20、tion in people with type 2 diabetes by performing a blood test and measuring cystatin C levels. This finding is an advancement in the way that kidney function is monitored. Current methods for estimating glomerular filtration rate based on the measurement of creatinine are not accurate across the fu

21、ll spectrum of filtering capacity displayed by the kidneys of people wih diabetes. These creatinine-based melthods also require a calculation that is based on age and gender. We have shown for the first time that people wih diabetes and impaired kidney filering capacity have a greater burden of dise

22、ase affecting the arateries within the kidney compared to those with normal filtering capacity. In particular, the intrarenal arteries of subjects with diabetes and impaired kidney function are stiffer than the arteries in people with normal kidney function. Our preliminary biopsy results suggest th

23、at the structural changes seen within the kidneys of people wilth diabetes and non-albuminuric chronic kidney disesae (CKD) are different to those seen in subjects with CKD associated with micro- or macro-albuminuria. Although there is a fair degree of overlap between the structural changes seen in

24、non-albuminuric and albuminuric subjects with CKD, we have not seen the classical structural changes of diabetic nephropathy in non-albuminuric subjects. In contrast, subjects with non-albuminjuric CKD have kidney biopsy samples that display changes ranging from mild to advanced arteriosclerosis. Th

25、ese findings potentially suggest that therapies targeting arterial disease and arterial stiffness may improve kidney function in people with diabetes and either albuminuric or non-albuminuric renal insufficiency.Expected future outcomes:We expecat that methods for estimating glomerular filtration ra

26、te (GFR) based on cystatin D along with the measurement of urinary albumin excretion (AER) will emerge as the expected standard of care for monitoring kidney function in subjects with diabetes. Our findings should also provoke clinical trials of therapies that target arterial disease and arterial st

27、iffness.Name of contact: George JerumsEmail of contact: ah-endo.auGrant ID: 385004Start Year: 2006CIA Name: A/Pr Zeinab KhalilEnd Year: 2008Main RFCD:Therapies and Therapeutic TechnologyTotal funding: $407,924.00Admin Inst: Austin Hospital Medical Research FoundationGrant Type: NHMRC Project GrantsT

28、itle of research award: A novel sensory nerve stimulator to improve neuropathy in patients with diabetesLay Description (from application):We have developed a painless, self-applied, cheap, battery powered electrical stimulation treatment that improves sensory nerve function in some people with diab

29、etic peripheral neuropathy. We have tested this technique in laboratory animals and in people with diabetes and have shown it is effective in some. We now propose to test this technique in a large sample of people similar to the participants in the successful group of our pilot study - 55-65 year ol

30、d people with diabetes of shorter duration. In addition, older people up to 75 years of age, with up to 10 years duration of diabetes will be included separately. If successful, the electrical stimulation could improve sensation leading to fewer ulcerations and amputations. Much suffering and expens

31、e would be avoided. - The magnitude of reduction in suffering and expense can be judged from the fact that people with diabetes have 15 times the risk of amputation as do people without diabetes. In Australia half of non-traumatic amputations are done to people with diabetes. Foot ulcers precede amp

32、utations in most cases, and in themselves cause much suffering and expense. Australia needs to act on this now because, if current trends continue, the number of people with diabetes will increase as the population ages. -The number of people aged over 65 will increase from around 2.3 million at pre

33、sent to over 6 million in the next half century. The increase in those over 85 will be even more marked with numbers increasing four fold to over one million people. Diabetes affects approximately 23% of people aged 75 or older.Research achievements (from final report):By 2051, it is estimated there

34、 will be 6 million Australians over the age of 65. Among people aged 65-74 some 20% are diagnosed with Diabetes Mellitus (DM). Many of those older patients suffer from the complications of DM, which increase with increasing duration of DM, with lower extremity amputation (LEA) being a significant co

35、mplication of the disease. The primary aim of this research is to test the a novel treatment, Low Frequency Sensory Nerve Stimulation (LF-SNS), to reduce neuropathic symptoms in people with diabetic peripheral neuropathy (DPN), and to improve sensory nerve function thus reduce DPN and consequently l

36、eg ulcers. We recently finalised data collection (end of May 2009) and broke the study code. The statistical analyses to date show that the use of the relatively inexpensive, non-invasive, LF-SNS technique for 12 weeks resulted in improvement in:osensory nerve function that is demonstrated by improv

37、ements in skin microvascular blood flow, time to initial flare and area of flare to capsaicin as well as C fibres perception threshold.o diabetic peripheral neuropathy shown by both objective (Neuropathy impairment score) and subjective (Neuropathy symptoms profile) measures.The significance of the

38、project for Australians and the health care system: We were able to show that the inexpensive, non-invasive, self-applied, sensory nerve stimulation technique (LF-SNS) improves sensory nerve function and its continuous use could alleviate much burden of illness. It could potentially prevent the form

39、ation of diabetic foot ulcers, or speed their healing, through preventing or improving DPN. This would avert much suffering, including LEA, and health care expenditure. This study therefore provides evidence needed to induce alterations to clinical practice; to have LF-SNS incorporated into the stan

40、dard management of such conditions as DPN, thus improving health outcomes for many Australians and providing enormous health cost benefits.Expected future outcomes:Further research should look more fully into the effects LF-SNS has on aged skin. Since the current study showed that C-fibre function i

41、mproves with this therapy and as these nerves are necessary to maintain skin integrity, then the regular use of LF-SNS may well help maintain (if not improve) skin integrity in the older population. This in turn may help prevent the formation of ulcers.Name of contact: Zeinab KhalilEmail of contact:

42、 zeinab.auGrant ID: 250399Start Year: 2003CIA Name: A/Pr Denise JacksonEnd Year: 2005Main RFCD:Immunology not elsewhere classifiedTotal funding: $265,500.00Admin Inst: HYPERLINK l AustinResearchInstitute Austin Research InstituteGrant Type: NHMRC Project GrantsTitle of research award: Regulating tol

43、erogenic signals by inhibitory co-receptorsLay Description (from application):Immunoreceptors play an important role in balancing the threshold of cellular activation is critical in the immune response to tumours, pathogens or allergens, to arrest autoimmune and infectious disease and to provoke imm

44、unological memory to vaccination. We have discovered that Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1/CD31) is a new immunoreceptor, that belongs to a very important family of proteins, the Ig-ITIM superfamily which is a subset of the immunoglobulin superfamily. We wish to determine if PE

45、CAM-1 functions as an inhibitory receptor in the lymphoid microenvironment using genetically engineered mice which lack the protein. As some of the functional features may display modest features, we plan to cross the PECAM-1 deficient mice with hen egg lysozyme transgenic mice to test the importanc

46、e of PECAM-1 in peripheral tolerance. We will also define its importance in T cell function. We will test if the PECAM-1 deficient mice are more susceptible to the onset of inducible autoimmunde diseases including mouse models of collagen-induced arthritis and diabetes. Finally, we will produce tran

47、sgenic mice expressing normal and disabled signaling motifs of PECAM-1 to test their requirement in autoimmunity.Research achievements (from final report):Our studies clarified the unique role of a new inhibitory co-receptor, PECAM-1 in the context of immunity and tolerance. In PECAM-1-/-.sHEL+/+.Ig

48、HEL+/- mice, elevated levels of anti-HEL immunoglobulin M (IgM) antibodies in the serum of PECAM-1-/- mice transgenic for both an HEL-specific B cell receptor (BCR) and soluble lysozyme was observed at six weeks compared to PECAM-1+/+.sHEL+/+.IgHEL+/- mice. Anergic B cells lacking PECAM-1 showed enh

49、anced B cell proliferation and calcium flux responses to LPS, IL-4 alone and IgM cross-linking and IL-4 indicating augmentation of antigen receptor signalling. Thus, PECAM-1 is important in maintaining peripheral tolerance in anergic B cells.(DJ35).Specifically, the absence of PECAM-1 results in a m

50、odest maturation defect of CD8+ T cells. PECAM-1-/- mice have normal susceptibility to DTH responses induced by KLH. PECAM-1-/- T cells are hyper-proliferative to anti-CD3 and anti-CD28 stimulation (T cell proliferation and MLR reactions) consistent with involvement of ITAM-associated TCR signalling

51、 pathway. PECAM-1-/- mice show enhanced in vivo and in vitro deletion of double positive thymocytes following challenge with anti-CD3 (2C11), dexamethasone and gamma-irradiation treatment consistent with a role for PECAM-1 in apoptosis (DJ26).We have demonstrated that PECAM-1 serves a protective rol

52、e in the early development of active models but not passive transfer models of collagen-induced arthritis (DJ31).We initially generated transgenic constructs containing wild-type and ITIM mutant forms of mouse PECAM-1 fused to the H-2Kb promoter. We have now developed transgenic mouse lines containi

53、ng ITIM mutant forms of mouse PECAM-1. We have confirmed authenticity of the transgene. We are currently characterising these transgenic mouse strains (molecular and protein level) and crossing them onto PECAM-1 knockout background. These transgenic mice will be used to study PECAM-1s role in immuni

54、ty and tolerance.Expected future outcomes:The importance of immune inhibitory receptor modulation has been demonstrated by fatal autoimmune disorders observed in mice with targeted disruption of inhibitory receptors. Intracytoplasmic ITIMs are highly conserved throughout evolution and are proving to

55、 be essential for terminating immune responses. Our studies will clarify the unique role of inhibitory co-receptors in immunity & tolerance.Name of contact: A/Prof. Denise JacksonEmail of contact: d.jackson.auGrant ID: 418101Start Year: 2007CIA Name: Prof Geoffrey FarrellEnd Year: 2009Main RFCD:Hepa

56、tologyTotal funding: $449,592.00Admin Inst: HYPERLINK l AustralianNationalUniversity Australian National UniversityGrant Type: NHMRC Project GrantsTitle of research award: MECHANISMS OF DISORDERED HEPATIC LIPID PARTITIONING IN NON-ALCOHOLIC STEATOHEPATITISLay Description (from application):Fatty liv

57、er is the commonest form of liver disease. It is strongly associated with obesity and maturity onset diabetes. The majority of cases of fatty liver disease cause no complications, but when inflammation and liver damage also occur, in the condition of non-alcoholic steatohepatitis or NASH, liver scar

58、ring and eventually cirrhosis or liver cancer can result. The reason why some people with fatty liver disease develop NASH and others do not (benign or simple steatosis) is unknown and is the subject of this research. The studies will be performed in a novel mouse model of obesity and diabetes, the

59、fat aussie mouse, in which all animals develop fatty liver disease after a few months. When fat aussie mice are fed a Macdonalds diet high in saturated fat they develop full-blown NASH with liver scarring. Before NASH develops in fat aussie mice, blood levels of adiponectin (a protein produced from

60、fat storage cells) fall. Together with high blood insulin and high blood sugar levels, it is proposed that these changes are what leads to an extraordinarily high build up of fat (lipid) molecules in the liver, to the extent that the fat ultimately damages the liver in a process called lipotoxicity.